Glioma stem cells remodel immunotolerant microenvironment in GBM and are associated with therapeutic advancements

Fei, Xifeng; Wu, Jie; Tian, Haiyan; Jiang, Dongyi; Chen, Hanchun; Yan, Ke; Wang, Yuan; Zhao, Yaodong; Chen, Hua; Xie, Xiangtong; Wang, Zhimin; Zhu, Wenyu; Huang, Qiang

doi:10.3233/CBM-230486

Glioma stem cells remodel immunotolerant microenvironment in GBM and are associated with therapeutic advancements

Article type: Research Article

Authors: Fei, Xifeng^{a; 1} | Wu, Jie^{b; 1} | Tian, Haiyan^{c; 1} | Jiang, Dongyi^a | Chen, Hanchun^a | Yan, Ke^b | Wang, Yuan^d | Zhao, Yaodong^e | Chen, Hua^f | Xie, Xiangtong^a | Wang, Zhimin^{a; g; *} | Zhu, Wenyu^{b; *} | Huang, Qiang^h

Affiliations: [a] Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China | [b] Department of Neurosurgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing University Medical School, Suzhou, Jiangsu, China | [c] Department of GCP, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China | [d] Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China | [e] Department of Neurosurgery, Shanghai General Hospital, Shanghai, China | [f] Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China | [g] Department of Neurosurgery, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China | [h] Department of Neurosurgery, Second Affiliated Hospital of Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China

Correspondence: [*] Corresponding authors: Wenyu Zhu, Department of Neurosurgery, the Affiliated Suzhou Science and Technology Town Hospital of Nanjing University Medical School, Suzhou 215163, Jiangsu, China. E-mail: [email protected]. Zhimin Wang, Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou 215127, Jiangsu, China. E-mail: [email protected].

Note: [1] Xifeng Fei, Jie Wu and Haiyan Tian contribute equally to the article.

Keywords: Glioma stem cells, niche, glioma cold environment, immunotherapy, GBM models

DOI: 10.3233/CBM-230486

Journal: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-24, 2024

Received 15 November 2023

Accepted 19 July 2024

Published: 4 August 2024

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Abstract

Glioma is the most common primary tumor of the central nervous system (CNS). Glioblastoma (GBM) is incurable with current treatment strategies. Additionally, the treatment of recurrent GBM (rGBM) is often referred to as terminal treatment, necessitating hospice-level care and management. The presence of the blood-brain barrier (BBB) gives GBM a more challenging or “cold” tumor microenvironment (TME) than that of other cancers and gloma stem cells (GSCs) play an important role in the TME remodeling, occurrence, development and recurrence of giloma. In this review, our primary focus will be on discussing the following topics: niche-associated GSCs and macrophages, new theories regarding GSC and TME involving pyroptosis and ferroptosis in GBM, metabolic adaptations of GSCs, the influence of the cold environment in GBM on immunotherapy, potential strategies to transform the cold GBM TME into a hot one, and the advancement of GBM immunotherapy and GBM models.

1.Introduction

Figure 1.

All tumors lacking IDH mutations with concomitant gain of chromosome 7 and loss of chromosome 10, EGFR amplification, or TERT promoter mutations are referred to as glioblastomas.

Glioblastoma multiforme (GBM) is the most common intracranial malignant tumor, and its prognosis has not made significant progress, despite the advances in treatments. In the 2021 edition of the WHO classification, gliomas lacking IDH mutations that have concomitant +7/-10 chromosome copy number changes, EGFR gene amplification, or TERT promoter mutations are called glioblastoma and are given a WHO grade of 4 [1] (Fig. 1). Glioma stem cells (GSCs) in GBM are a small group of cells with low proliferative activity and drug resistance that are associated with tumor recurrence and are at the root of GBM refractoriness and recurrence. In most instances, these GSCs may be already progenitor cells for differentiation when they remodel the host tissues, and we refer to them as glioma stem/progenitor cells (GSPCs) [2]. The incidence of most cancers, including GBM, rose between 2018 and 2020 [3], outstripping increases in survival rates, and with only few cancers, such as melanoma, showing improvement due to immunotherapy [4, 5]. In contrast to the “hot” melanoma tumor microenvironment (TME), the “cold” GBM TME and the presence of the blood-brain barrier (BBB) which limits drug passage [6, 7], and, complicate treatment advances. Recent studies show that neuroinflammation creates an immunomodulatory niche in the meningeal lymphatic vessel system close to the cribriform plate in which cerebrospinal fluid drainage kinetics are reduced with aging [8, 9, 10] and the immune cells contained in the lymphatic fluid are currently the focus of attention. Current research is focused on enhancing pyroptosis and ferroptosis in GBM cells as a strategy to convert the cold GBM tumor microenvironment into a hot one. Then with the help of single-cell sequencing to screen regulatory molecules, study prognosis and develop targeted therapies to improve the efficacy of GBM immunotherapy [11, 12, 13, 14, 15]. Although immunotherapy shows some advantages to improve the quality of life and survival prognosis of GBM patients, much work is necessary to optimize immunotherapy for GBM patients. While we have briefly outlined these issues, we will now delve into a more detailed description of the molecular support and regulatory mechanisms involved in the immunotolerant microenvironment remodeled by GSCs in GBM.

2.Glioma stem cells and immune-related niches

2.1TME and glioma stem cells

A tumor is a complex system comprising both tumor cells and various non-tumor cells, and the TME is a direct representation of this intricate system. The TME consists of cancer cells surrounded by diverse non-malignant cell types, such as cancer-associated fibroblasts, endothelial cells, pericytes, and other cell types that can differ based on the tissue, like adipocytes and neurons. Throughout various stages of tumor development, including initiation, progression, invasion, intravasation, metastatic dissemination, and outgrowth, the TME and its cells play a crucial role. Immune tolerance in the tumor microenvironment leads to immune escape from therapy, which is mainly due to the ability of tumor stem cells to remodel the tumor’s immune microenvironment [16]. Interaction of CSCs with their niche is critical for tumor immunosuppression and tumor recurrence. Moreover, it was demonstrated that a high-stemness signature related to a poor immunogenic response across 21 solid malignancies. Most notably, CSCs are able to recruit tumor-associated immune cells such as monocytes and macrophages, and these immune cells can play a role in promoting tumor progression due to the remodeling of the tumor microenvironment [17]. As a result, conducting systematic research on cancer stem cells and other related cells within the TME will be a vital approach in identifying new targets for treating malignant tumors [18].

In glioma, the TME includes not only tumor cells but also immune cells, endothelial cells, glial cells, and neuronal cells. GSCs can remodel the immune-tolerant microenvironment of gliomas regardless of tissue cell type, and immune-inflammatory cells in the tumor microenvironment are even capable of undergoing malignant transformation through the remodeling of glioma stem cells, which leads to changes in immune tolerance and heterogeneity of tumors by a mechanism that may be related to cell fusion [19]. Furthermore GSCs promote tumor angiogenesis and remodel the microenvironment of GBM by secreting histamine [20]. GBM has the ability to recruit normal cells from its surroundings to support its growth, maintenance, and invasion into the brain. Studies have demonstrated that the microenvironment in GBM varies depending on factors such as the isocitrate dehydrogenase status (mutated/wild type), the presence or absence of codeletion, and the expression of specific alterations like H3K27 and/or other gene mutations [21]. Recent investigations using Single-cell RNA sequencing (scRNA-seq) in high- and low-grade gliomas have revealed that intratumoral heterogeneity and dynamic plasticity across different cellular states are characteristic features of malignant brain tumors. As the tumor grade increases, there is an observed increase in the proliferation of malignant cells, larger populations of undifferentiated glioma cells, and a shift towards a higher expression of macrophage programs in the tumor microenvironment, compared to microglia expression programs [22].

Figure 2.

Schematic diagram of GSCs and immune-related mechanisms: A. Tumor entities, including the hypoxic niche and cell necrosis niches caused by tumor cell pyroptosis and ferroptosis and the macrophage niche, involved in adaptive immunity in the tumor microenvironment. B. The jagged and vague tumor periphery mediates tumor cell invasion and dissemination and marginal ecological niches are colonized here. C. Inflammatory necrotic cells located in the tumor necrosis zone caused by pyroptosis and ferroptosis. D. Hippocampus-subependymal neural stem cell niche: Maintenance and expansion of hippocampal- and subventricular-derived neural stem cells follow both symmetric and asymmetric disaggregation patterns to maintain homeostasis of glial-associated downstream cells in normal brain tissue, which in the case of GBM are largely replaced by the associated tumor stem cell niche. At this point, tumor cells may reverse-differentiate into GSCs.

Human GSCs in adult and child were first reported in 2003 by Singh SK [23], and in 2006 by Quanbin Zhang, respectively [24], and their mysteries have not yet been fully unveiled. The existence of GSCs can be a subject of debate, and the answer to whether they exist or not depends on various factors and perspectives. The stem cell marker CD133 expressing cells which are identified as GSCs in experiments tend to express the progenitor marker Nestin simultaneously [24], thus they are actually progenitor cells that have initiated the differentiation process. Real GSCs are treatment-resistant, quiescent and pluripotent and reside in a niche determined by the adaptive GBM immune microenvironment (Fig. 2A and 1B). The mystery lies in the fact that if the same cells are traced by only CD133 single positive fluorescent staining but not by CD133 and Nestin double staining, they may be GSPCs, rather than GSCs [2, 25]. As of today, there are still cells that are discreetly referred to as GSC-like cells, rather than being explicitly labeled as GSCs. This distinction reflects ongoing debates and complexities in the field of glioma research [26]. In fact, as early as 2011, GSCs were defined as those cells capable of driving tumor formation and spreading by differentially labeling human GBM cell components in a xenograft model and following tumor development using a living microscope [27]. GSCs have also been reported as capable of differentiation into offspring cells which may reverse-differentiate into stem cells [24] (Fig. 2D). This is not consistent with the view of Singh SK [28], who cloned GSCs from pediatric GBM and stated that GSCs originated from resident neural stem cells (NSCs) of the host hippocampus or under ependyma and differentiate irreversibly [23]. Subsequent research appeared to provide evidence supporting the concept of reverse-differentiation in GSCs [24]. This suggests that GSCs may possess the ability to revert back to a less differentiated state, adding further complexity to our understanding of these cells and their role in glioma. Furthermore, new CD133⁺ cells were detected in the in vitro cell cultures of rat glioma C6 after all CD133⁺ had been removed and defined most C6 cells as GSCs [29]. The potential for C6 cells to reverse differentiate into GSCs now seems a more realistic possibility. Under the conditions at the time, this reverse differentiation observation was not comprehensive enough, and the potential stem cell microenvironment, especially the Niche, was proposed later and is still a hot topic today.

2.2Stem cell niche

Studies conducted on Drosophila have contributed to the introduction of the concept of the niche [30], and in many instances, niches have been observed to be located in close proximity to the endothelium of blood vessels [31]. The understanding of its function has improved with the deeper research. Our research of GSCs transdifferentiating into vascular endothelial cells [25, 32] was published in 2011, ahead of similar reports by Wang R [33] and Ricci-Vitiani L [34], and exciting commentary by Victoria L Bautch [35]. Nowadays, it is understood that this transdifferentiation process may occur within the hypoxic periarterial niche of GSCs [36]. The GSC niche may also be subdivided into perivascular, peri-hypoxic, immune extracellular matrix and GBM peri-invasive sectors [37, 38, 39, 40, 41], the functions of which remain obscure except as an adaptive GBM immune microenvironment. The niche regulates angiogenesis and protects the GSC from radiotherapy and chemotherapy, driving recurrent GBM (rGBM) [42, 43]. Macrophage niches are similar to the adaptive immune microenvironment of GBM.

2.3Macrophage niche and tumor-associated macrophages

Researchers believe that the macrophage niche (mNiche) can be characterized by four fundamental functions: (1) providing a physical foundation or scaffold for the macrophage; (2) supplying nutritional factors to support the macrophage’s self-maintenance ability; (3) imparting the tissue-specific identity to the resident macrophage within the niche; and (4) the macrophages, in turn, should provide benefits to their niche. The mNiche plays an important role in tumor progression. mNiche is found throughout all mammalian organs. In addition to their role as immunesentinels, macrophages perform day-to-day functions essential to tissue homeostasis. mNiche maintains tissue homeostasis of macrophage, controls the macrophage population size and imprints their tissue-specific identity [41]. The mNiche has attracted attention for its potential therapeutic value. Previously, competition between macrophage precursors was proposed for development into resident macrophages in a limited number of niches [44]. Tight regulation ensures that monocytes differentiate into multiple heterogeneous macrophages only when niche space is available.

Nevertheless, the study of mNiche in tumors is still in its early stages, but significant progress has been made in understanding tumor-associated macrophages (TAMs). TAMs are the most abundant immune cells present in tumor tissues and are typically classified into two distinct subtypes: M1 macrophages and M2 macrophages [45].

M1 macrophages are known for their anti-tumor functions, whereas M2 macrophages have the opposite effect, promoting tumor development, metastasis, and inhibiting the anti-tumor immune response mediated by T cells. Additionally, M2 macrophages facilitate tumor angiogenesis and contribute to tumor progression. As a result, TAMs have become a promising target for tumor therapy [45].

In gliomas, similar to other solid tumors, the infiltration of TAMs is a notable characteristic. In GBM, TAMs are significantly elevated, as confirmed through bioinformatics studies. Higher levels of TAMs are associated with a decreased overall survival rate in glioma patients, suggesting that increased TAMs may be one of the mechanisms involved in immune escape in GBM. These findings indicate that TAMs-related signatures can serve as valuable prognostic biomarkers in GBM [46].

In addition to the presence of mNiche, the immune microenvironment of GBM is more complicated than in that of extracranial cancers such as the cold immune microenvironment.

3.The cold GBM immune microenvironment resists the immune response

3.1Cold immune microenvironment of GBM

Cancers may be classified as “hot” when there is a large T cell and inflammatory response after immune checkpoint inhibitor treatment, “warm” or “cold” when there is little response to treatment [47]. For example, approximately 50% of melanoma patients respond to the combined blockade of the immune checkpoint PD-1 and CTLA-4, 75% of whom have a long-lasting response [48]. Thus, melanoma is a hot tumor type. Conversely, Glioblastoma is a cold tumor, mainly because of immune tolerance in the GBM microenvironment. Compared to other tumor types, glioblastomas have relatively few tumor-infiltrating lymphocytes (TILs), and those that are present have been shown to be highly expressive of exhaustion markers. The glioblastoma microenvironment is characterized by the presence of a large number of myeloid cells, such as microglia and macrophages, which have immunosuppressive activity. In addition, defects in antigen-presenting mechanisms can make the tumor cold in response to T-cell-dependent immunity. Finally, necrosis in glioblastoma plays an important role in weakening the anti-tumor immune response [47]. Only 10% of GBM patients have a short-lived response to immunotherapy [49, 50]. The concept of transforming a “Cold” tumor into a “Hot” one is a novel area of research in tumor immunotherapy (IO). However, the impact of intratumoral injection of tilsotolimod, an oligodeoxynucleotide Toll-like receptor 9 (TLR9) agonist, in patients with advanced melanoma has not been conclusively determined [51], suggesting that traditional research approaches still have limitations. Fortunately, quantitative systems pharmacology modeling in cancer immunotherapy holds great promise in addressing major challenges in the IO field [52].

3.2Exploration for GBM cold environment

In the case of GBM, immunotherapy research has not stopped because of the cold immune microenvironment. Preclinical GBM models suggest Antigen-primed T cells could accumulate in brain tumors through healthy tissue tracking [53], and execute cytotoxic function with cellular precision [54], as well as adapt to a tumor’s evolving molecular profile via epitope spreading. Antitumor CD8 T cells can be controlled by PD-1/PD-L1 interactions [55]. PD-1 blockade augmented the anti-tumor CD8 T cell response, allowing the formation of memory T cells with the ability to prevent delayed tumor outgrowth [56]. In summary, data from preclinical models indicated the potential for GBM immunotherapy [56, 57, 58, 59, 60] but clinical trials have proved unsuccessful [61]. The phase III clinical trial of the anti-PD-1 monoclonal antibody, nivolumab, and the anti-growth factor VEGF-A monoclonal antibody, bevaci-zumab, for rGBM was terminated. However, Jackson, et al. considered that the cold nature of GBM may be converted into hot [62]. Recently, GBM cold tumors were divided into two subtypes with immune tolerance or immunodeficiency from data in the TCGA-GBM transcription database and the GEO dataset [63]. Tumor-associated macrophages were indicated as promising new therapeutic targets and GIPS as a biomarker for assessing the immune evasion mechanism, immunotherapy response and patient prognosis.

3.3Can microglia/macrophages turn cold GBM hot?

Resident tissue macrophages (RTMs) proposed by Blériot C [64] appear to be much more reasonable than those of macrophages in the tumor tissue microenvironment simply divided into M1 and M2 proposed earlier [50, 65]. The heterogeneity of RTMs includes four characteristics: cell origin, local environment, inflammatory state and residence time in tissues that contributes to the resilient adaptation of macrophages to their dynamic environment [64]. Brain RTMs also present these characteristics, in addition to the blood-brain barrier [66, 67, 68] and the cerebral lymphatic system [69, 70, 71]. Microglia are a unique tissue-resident macrophage population that plays an important role in maintaining the tissue homeostasis of the CNS [72]. Its characteristics and functions are mediated by Sall1, SMAD2/3, IRF8, Nr4a1 (Nur77), Nr4a2 (Nurr1) and Nr4a3 (Nor1). Nr4a1 (Nur77) can downregulate the transcription of thyroxine-hydroxylase by recruiting the CoREST complex involving HDAC1 and HDAC2 enzymes in the TH promoter region [73, 74, 75, 76]. Mice lacking Nr4a1 had poor prognosis and had high concentrations of norepinephrine (NE), pro-inflammatory IL-6, and autoimmune effector T cells at the site of the affected tissue area in the CNS, which was also necessary for GBM to switch from cold to hot. Thus, we may deduce that if a similar experiment is performed in a GBM mouse model, transcriptomic sequencing of the tumor and myeloid precursor derived macrophages may enable identification turnoff factors responsible for turning cold GBM into a hot tumor. Appropriate sequencing targets would be those concerned with initiation of pyroptosis or ferroptosis, which can trigger an acute inflammatory response. Hence, there is a reason to be optimistic about the search for regulatory molecules that could potentially transform GBM from a cold tumor microenvironment to a hot one.

4.Pyroptosis and ferroptosis

4.1Pyroptosis, PP

Thornberry NA [77] observed cysteine aspartase [caspase]-1-mediated programmed cell death, of a form morphologically distinct from apoptosis [AP], but of unknown mechanism in 1992. By 2015, PP effect is initially understood after gasdermin D (GSDMD) cleavage target of caspases-1 and -11 was discovered [78, 79]. PP was shown to be mediated by a pro-inflammatory caspase effect which caused cell death by cell membrane rupture and cell disintegration and was an anti-infective mode of inflammatory cell death against pathogens [63, 80, 81, 82, 83, 84, 85, 86, 87]. Chemical disruption of GSDMD was found to inhibit inflammatory cell death and activate IL-1 secretion by macrophages [88, 89]. More recently, methods to regulate its activity have recently been investigated. Succinate and disulfiram have been found to inactivate GSDMD to control PP and Ragulator-Rag complex has been found to be necessary for GSDMD pore formation and pyroptosis in macrophages [90, 91, 92]. Thus, mediation of PP centers around the inflammatory caspase substrate, GSDMD, which releases GSDMD-N and GSDMD-C domains on lysis, leading to PP by forming membrane pores. The extensive gasdermin family is composed of GSDMA, GSDMB, GSDMC, GSDMD, GSDME/DNFA5 and PVJK/GSDMF of which Gasdermin E shows promise as a potential target for disease therapy [93, 94].

4.2Glioma pyroptosis (GPP)

Recent interest in GPP [95, 96, 97, 98, 99] has focused on TCGA and CCGA database bio-informatics-selection of genes and non-coding RNA (ncRNAs) associated with GPP and glioma prognosis [100, 101, 102]. Indeed, copy number variation and somatic mutation of 33 PP-related genes have been associated with GBM survival prognosis and a prognostic model constructed from 7 PP-related genes for validation in the CGGA cohort [95]. Moreover, CASP8, CASP4, CASP1, NLRP3, NLRP1 and NLRC4 have been identified as hub genes that divide gliomas into two subtypes with good and poor prognoses [96]. Fifteen scorch-death-related genes predicted overall glioma survival and nine pairs of target genes and drugs were identified. Genes encoding caspase 3 and IL-18 have been suggested as a potential prognostic biomarkers for overall survival of patients with diffuse gliomas [97]. Patients in the high-risk subgroup had shorter survival times than those in the low-risk subgroup. GSEA and ssGSEA showed the activation of immune-related pathways and the extensive infiltration of immune cells in high-risk subgroup. The prognostic value of PP-related gene expression in infiltrating immune cells has been indicated [98] in addition to glioma prognosis models of PP-related genes [99] and PP-related ncRNAs, including miRNA, lncRNA and circRNA, have also been implicated [100]. Most circRNAs are highly conserved and exon-derived with a few arising from intron cyclization. They may be classified as follows: exon circRNA (ecRNA), cyclic intron RNA (ciRNA), exon-intron circRNA (EIciRNA) and tRNA intron cyclic RNA (tri RNA) [103]. Expression of circRNA varies with developmental stage and is tissue-specific. Because circRNA is insensitive to nuclease and more stable than linear RNA, circRNA has obvious advantages in the development and application of new clinical diagnostic markers, such as the autophagy-associated circRNA, circCDYL [104] and other circRNAs have been linked to cancer cell ferroptosis [105], tumorigenesis [106], tumor metabolism [107] and drug resistance [108].

4.3Ferroptosis and glioma immunity

Ferroptosis, similar to PP described above, is different from AP, but rather a recently highly concerned, new form of cell death that plays an important role in the occurrence and development of many diseases. The comprehensive introduction from the past, present and future of ferroptosis research written in 2020 lacked relevance to glioma [109] However, by 2021, Fe deficiency-related genes was proved to predict prognosis and immunotherapy in glioma., and the prognostic ferroptosis-related lncRNAs in glioma were associated with the immune landscape of glioma microenvironment and radiotherapy response [110, 111]. Furthermore, the characterization of a ferroptosis signature has been employed to assess the predictive prognosis and potential effectiveness of immunotherapy in glioblastoma [112], Additionally, a prognostic risk model has been developed using seven Fe deficiency-related genes for low-grade glioma (LGG), considering their implications for immunotherapy [113]. The utility of ferroptosis for GBM and LGG research is thus demonstrated.

Ferroptosis has also been shown to be responsible for glioma-associated immunogenic cell death [114, 115, 116]. The immunogenicity of ferroptosis in vitro and in vivo was first demonstrated by the induction of ferroptosis by RAS-selective lethal compound 3 (RSL3) in mouse fibrosarcoma MCA205 or glioma GL261 cells. Ironophils promoted bone marrow-derived dendritic cell (BMDC) phenotype maturation and elicited a vaccination-like effect in immunocompetent mice suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent [117]. RNA-sequencing was used to construct a prognostic risk score model (FRGPRS) related to GBM overall survival from Fe deficiency related genes. Further comparison of genomic and clinical features, immune infiltration, enrichment pathways, pan-cancer, drug resistance and immune checkpoint inhibitor therapy in different FRGPRS subgroups showed that five Hub genes in the FRGPRS could be used to predict overall and progression-free survival of GBM patients. High FRGPRS was associated with strong immunity, higher tumor tissue ratio, good cytotoxic immunity and chemotherapy response in GBM patients [118]. The utility of ferroptosis for GBM treatment was also reported, and combination of Onofen and cold atmospheric plasmas could trigger AP, ferroptosis and immunogenic responses in GBM [119, 120]. Temozolomide was found to precipitate ferroptosis through dmt1-dependent pathways [121] and the ferroptosis inducer, disulfiram, could trigger lysosomal membrane permeability by upregulating ROS and enhanced the radiosensitivity of GBM cells [122]. Recently, scholars rediscovered from transcriptomic data that CYBB and SOD2 genes were significantly up-regulated in the mesenchymal subtype of GBM. In GBM cells that are resistant to the chemotherapy drug TMZ, they exhibit mesenchymal and stemness characteristics while also displaying resistance to ferroptosis, a type of cell death caused by iron-dependent oxidative stress. This resistance to ferroptosis is achieved through the activation of the CYBB/Nrf2/SOD2 axis. As a result, CYBB plays a crucial role in conferring ferroptosis resilience in mesenchymal GBM. The downstream compensatory activity of CYBB, achieved through the Nrf2/SOD2 axis, presents an opportunity for exploiting a potential strategy to overcome TMZ resistance by modulating ferroptosis. This finding holds promise for the development of new approaches to tackle drug resistance in mesenchymal GBM [123].

In summary, PP and ferroptosis in GBM are confined to the cell necrosis region, followed by immune adaptation (Fig. 2C). However, the immune cells come from the CNS lymphatic system (Fig. 2E), and the brain has traditionally been regarded as immune-exempt and lacking a lymphatic system, a view that may require updating.

5.Metabolic adaptations of GBM

The metabolic abnormalities in glioma involve disruptions in sugar, protein, and fat metabolism. Recently, more attention has been directed towards studying the glycosylation of post-translational modifications of proteins. The differential expression of glycosyltransferase genes determines the type of glycosylation and epigenetically regulates the progression of glioma. Hypoxia, a well-known factor in gliomas, has been found to induce GLT8D1, which enhances stem cell maintenance in glioma by inhibiting CD133 degradation through N-linked glycosylation [124]. As a result of these findings, various changes in the biology, biomarkers, and targeted therapies for glioma have emerged [125]. Comprehensive analyses have identified glycosyltransferase signatures and prognostic long non-coding RNAs (lncRNAs) related to glycosylation from databases such as TCGA and CGGA [126]. These analyses can be used to evaluate the prognosis of glioma patients and construct prognostic models for overall survival [127].

GSC-specific histamine secretion has been found to drive proangiogenic tumor microenvironment remodeling. Histamine, a metabolite secreted by GSCs, is produced due to MYC-mediated transcriptional upregulation of histidine decarboxylase (HDC) through GSC-specific H3K4me3 modification. GSC-secreted histamine promotes angiogenesis and GBM progression by activating endothelial cells through the histamine H1 receptor (H1R)-Ca2+-NFkB axis [128]. Interestingly, the role of histamine in the GBM microenvironment is opposite to that in the peripheral blood, where histamine triggers a positive immune response. The blood-brain barrier limits the entry of peripheral blood histamine into the GBM microenvironment, making the role of histamine-driven pro-angiogenic tumor microenvironment remodeling particularly noteworthy. Another important factor of concern is the MYC oncogene, which is often referred to as a “Superoncogene” due to its powerful role in regulating GBM metabolism [129]. The understanding of MYC has evolved over the years, and it is now known to control gene expression at multiple levels, including directly binding to chromatin and recruiting transcriptional coregulators, regulating RNA polymerase activity, and more. GBM is characterized by Myc deregulation and undergoes significant metabolic changes to meet the increased energy demand. Conversely, cancer metabolism disorders also impact MYC expression and function, making MYC a crucial link between metabolic pathway activation and gene expression. Ongoing and future studies will focus on controlling the Myc oncogene and exploring new treatments for GBM by targeting metabolic pathways to deprive tumor cells of nutrients through inhibiting MYC expression [129]. In summary, metabolic adaptations in GBM play a vital role in its malignant progression.

6.The immune system in the normal brain and the lymphatic system in GBM

Lymphatic vessels do not exist in human brain in medical cognition for a long time. However, as early as 2015, discharge of cerebral interstitial fluid and macromolecules by the dural lymphatic system and structure and function of CNS lymphatic vessels were described [130, 131]. Meningeal lymphatic vessels at the skull base were proved to involve in the clearance of cerebrospinal fluid (CSF) and neuroinflammation-induced lymphangiogenesis near the cribriform plate was showed to contribute to drainage of CNS-derived antigens and immune cells in 2019 [132, 133]. Furthermore, untill 2021, meningeal lymphatic vessels were found to regulate lymphatic drainage and immunity in brain tumors [134] and VEGF-c-dependent lymphatic drainage to participate in immune surveillance [135]. Finally, a complete CNS lymphatic system, encompassing arachnoid villi, periarangial pathways and dural lymphatic vessels and communicating with the cerebrospinal fluid has been proposed [136]. The view of immune exemption for the CNS has thus been considerably revised.

The situation is more complex in GBM and lymphatic outflow of cerebrospinal fluid in glioma is decreased [137]. Indeed, GBM cells inoculation proximal to the left ventricle (LV) in a mouse model disrupted the ependymal barrier and increased tumor-CSF interaction, negatively impacting immunotherapy. The author considered the occurrence of therapeutic targets in cerebrospinal fluid only if healthy ependymal membrane cells were present [138].

7.GBM immunotherapy

Table 1

Overview of immunotherapy modalities to glioblastoma

Immunotherapy modalities	Description
CAR-T cell therapy	Including IL13rα2 specific CAR-T, EGFRvIII CAR-T, HER2 specific CAR-T, B7-H3 specific CAR-T and CAR-NK immunotherapy
Immune checkpoint inhibitor therapy	PD-1/PD-L1 blocking therapy
Tumor vaccination	Including cell vaccines, synthetic peptide vaccine, and nucleic acid vaccine
Oncolytic virus therapy	Using intratumoral delivery of virus to TME for treatment, or causes direct cytotoxicity through viral infection and replication

Figure 3.

Current immunotherapy modalities for the treatment of glioblastoma: 1. CAR T-cell therapy such as anti-IL-13Rα2CART cell therapy, anti-EGFRvIII CART cell therapy, anti-HER2 CART cell therapy, anti-BFH3 CART cell therapy, and the relatively specific CAR-NK cell therapy; 2. Immune checkpoint inhibitor therapy, the most important of which is to inhibit the binding of PD-1 and PD-L1, thus restoring the tumor cell killing effect of CTL; 3. Vaccine therapies, including cellular vaccines, SPV and NAV, which can promote the tumor-killing effect of CTL; 4. Oncolytic virus therapies, are viruses that can selectively infect or replicate in tumor cells, which not only directly kill infected tumor cells, but also promote the tumor-killing effect of CTL.

The failure of phase III GBM immunotherapy clinical trials has been attributed to the targeting of a single anti-tumor component, ignoring the acknowledged heterogeneity of the environment [139]. Further research progress has been widely concerned. Successful advances in immune checkpoint blockade therapy and targeting immunosuppressive proteins, such as programmed cell death protein-1(PD-1) and/or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), have been reviewed [140], Initiating a paradigm shift in clinical and preclinical research and applied immunotherapy to solid tumors, which will be a potential breakthrough in the field of GBM drug treatment. However, resistance to GBM therapy has been ascribed to cancer stem cells (CSCs) and the inability of immunotherapy (IT) to completely eliminate CSCs results in failure to universally prolong patient survival [141]. A systematic IT approach to CSC elimination may provide a solution and progress has been made in CAR-T, immune checkpoint inhibitors, vaccination and oncolytic virus therapies for GBM (Fig. 3 and Table 1).

7.1CAR-T for gliomas

Chimeric antigen receptors (CAR) engineered T cell mediated adoptive immunotherapy (CAR-T) has made great progression in the treatment of hematological malignancies [142]. As far as GBM is concerned, as the peculiarities of the immune microenvironment described above, CAR-T has been of limited benefit for GBM, although preclinical models have furnished hope [143]. More research continues with the aim of improving CAR efficacy in GBM [144, 145]. The following three research approaches have been described.

7.1.1IL13rα2 specific CAR-T

Interleukin 13 receptor subunit α-2 (IL13Rα2) is present in 60 percent of GBMs and is associated with pro-inflammatory and immune pathway activation [146, 147]. Overexpression of IL13Rα2 in GBM patients results in the activation of phosphatidylinositol-3 kinase/AKT/rapamycin pathway, thereby leading to poor prognosis and increased tumor aggressiveness [148, 149]. Intracranial injection of IL13-zetakine CAR-T into tumor-bearing animals significantly prolonged survival [150] and the brain inflammation, grade 3 headache and transient grade 3 neurological events were controllable by infusion of IL13rα2-directed CAR-T cells through implanted container/catheter system into the tumor resection stumps. Decreased IL13 Rα2 tumor expression, persistently increased tumor necrosis volume observed during MRI and improved overall survival resulted from treatment [150]. Second-generation IL13-zetakine CAR-T cells for 6-cycle tumor residual infusion and 10-cycle ventricular system infusion (via lumbar puncture) were developed to treat one patient of rGBM. Residual intraluminal perfusion inhibited local tumor progression but extraluminal intracranial tumor progression and new spinal cord lesions were discovered. Although, the fifth ventricular infusion reduced intracranial and spinal cord tumors by 77–100% but only lasted 7.5 months. Recently, a novel TanCAR, comprising the tandem arrangement of IL13 (4MS) and EphA2 scFv, was reported to selectively kill GBM tumor cells, but did not kill normal cells bearing only the IL13Rα1/IL4Rα receptor. TanCAR T cells have proved more effective in glioma reduction than single IL13 CAR or EphA2 scFv CARs and prevent antigen escape reducing off-target cytotoxicity in a xenograft mouse model [151].

7.1.2EGFRvIII CAR-T and CAR-NK immunotherapy

The antitumor effects of EGFRvIII-specific CAR-T in in vitro and in vivo models of U87 cells were reported in 2013 [152]. It was later discovered that Infusion of CAR-modified T cell (CART)-EGFRvIII cells into ten recurrent GBM patients produced off-tumor toxicity or cytokine release syndrome and significant EGFRvIII -mediated CAR-T cells were found in peripheral blood [153]. Third generation EGFRvIII CAR-T (G3-EGFRvIII) increased IFN-γ levels on co-culture with glioma cells in vitro and prolonged survival in tumor-bearing mice [154] but controversies remain over clinical treatments based on EGFRvIII CAR-T due to EGFRvIII do not represent prognostic keys in EGFR-amplified glioma patients [155].

CAR-NK, a development based on CAR-T, is already a fourth-generation engineered cell, which has received as much attention as CAR-T, Fourth generation EGFRvIII specific CAR-NKs have been engineered [156]. Since EGFRvIII specific CAR-NK has been reported, a number of researchers [157, 158, 159, 160, 161] have demonstrated their results from different perspectives such as molecular mechanism and efficacy. Especially, MSCs can be home to GBM and not healthy brain cells, hence it serves as a tumour-specific drug-delivery system, including pro-apoptotic factors and tumor necrosis factor-related apoptosis-inducing ligands (TRAIL) [162]. Furthermore, the design of bi-functional MSCs expressing high levels of TRAIL and GD2 tCAR, which is associated with a robust anti-tumor activity against GD2-positive GBM cells, shows promise [163, 164].

7.1.3HER2 or B7-H3 specific CAR-T therapy

HER2 is highly expressed on GBM ependymoma and medulloblastoma, but not in normal CNS tissues [165]. HER2-specific T cells, which target primary glioblastoma stem cells, have demonstrated promising preclinical effects in 10 GBM patients [166]. In clinical treatment of 17 HER2-positive, progressive GBM patients, there were no dose-limiting toxic effects, and CAR-T cells were detected in the peripheral blood for up to 12 months after infusion. However, despite these findings, there was no notable expansion of CAR-T cells or significant survival benefit observed in these patients [167].

B7-H3 (also known as CD276) is a newly found molecule of B7 family. B7-H3 could promote the activation of T cells and the proliferation of IFN-γ. It is highly expressed in all most human cancers, associated with undesirable treatment outcomes and survival time, due to function of the immune checkpoint molecule. B7-H3 is frequently overexpressed in GBM patients, and its expression levels were correlated to the malignancy grade and poor survival in both low-grade glioma (LGG) and GBM patients. Therefore, it may serve as a valuable target for CAR-T therapy [168, 169, 170, 171, 172].

CAR-T research on both hematological and solid tumors has increased between 2009–2021 [173]. When it comes to GBM, including targets such as IL13Ra2, EGFRvIII, and HER2, there are challenges that need to be addressed. However, obstacles still exist, such as the high investment costs and a lack of cooperation among research units.

7.2Immune checkpoint inhibitor therapy

Immunotherapy, involved in various immune checkpoint inhibitor molecules, has improved patients’ survival in different types of cancers. This is one of the most hopeful approaches for antitumor therapy. Glioma immune checkpoints including PD-1/PDL-1, Tim-3/Galectin-9, CTLA4, LAG3 and TIGIT/CD96, are targets for immune checkpoint inhibitor therapy [174]. The anti-PD-1 and anti-PD-L1 monoclonal antibodies approved by the US FDA- block distinct inhibitory signals that unleash T cells to aid tumor eradication. T cells, B cells, TAMs, myeloid stem cells (MDSCs) and natural killer cells (NK) all target the PD-1/PD-L1 pathway in GBM to trigger an anti-tumor immune response. Tumor that has been immunosuppressed is removed first and then immunotherapy is used to enhance the functions of the tumor infiltrating lymphocytes (TILs). Unfortunately, the administration of checkpoint inhibitor therapy has shown limited success in GBM clinical trials, primarily due to the challenges of successfully delivering the drugs across the BBB. Some progress has been made since PD-1/PD-L1 blocking therapy was predicted to be the future for cancer immunotherapy in 2019 [175]. PD-L1-mediated GBM immunosuppression has been reported to be related with infiltration and M2 polarization of TAM [176], suggesting targeting both TAMs and mNiche as a promising strategy [44]. Indeed, CD137 and PD-L1 targeted immunoviral therapy has been shown to induce a lasting anti-tumor immune response in a malignant glioma model [177]. Follicular helper T cells have been found to restore CD8⁺-dependent anti-tumor immunity and anti- PD-L1/PD-1 activity [178]. For gliomas, the PD-1/PD-L1 axis and adenosine pathways have been found to be immunosuppressive [179] and TIGIT and PD-1 immune checkpoint pathways to be associated with prognosis and anti-tumor immunity [180]. Despite these promising results, we are still far from resolving the clinical challenges posed by the disease. Indeed, the prognostic value of bioinformatics in relation to immune checkpoint inhibition for GBM has been extensively studied [181, 182, 183]. Additionally, the inhibitory impact of engineered extracellular vesicle irradiation on GBM immune checkpoints has been reported [184], and all of these findings hold promise for potential clinical applications.

7.3Vaccination: Cell, peptide and mRNA vaccines for glioma

Cell vaccines: In addition to CAR-T and CAR-NK regarded as T and NK cell vaccines [185], Dendritic cell (DC) fusion vaccine is the most important cell vaccine. Bone marrow-derived DC fusion vaccines have been given to tumor-bearing mice, alone or in combination with telimazolid, to prolong survival time [186, 187]. Glioma stem cell-targeted dendritic cells as a tumor vaccine against malignant glioma and DC glioma cell fusion as an antitumor vaccine in vitro culture have also been studied respectively [188, 189]. In a large phase III clinical trial of DC vaccine for GBM, 331 patients with GBM after standardized treatment were included, patients were randomized to receive temozolomide plus DC vaccine (n= 232) or temozolomide and placebo (n= 99). The results showed that the addition of DC vaccine to standard therapy is both feasible and safe for patients, and it has the potential to extend survival. Only 2.1% of patients experienced a grade 3 or 4 adverse event [190]. Indeed, an almost complete response of GBM patients to treatment with an allogeneic dendritic cell-based vaccine was an encouraging outcome of a 2022 trial [191].

Synthetic peptide vaccine (SPV): TollR-3/poly-ICLC and TGF-β improved the therapeutic efficacy of glioma-associated antigen peptide vaccines on tumor-bearing mice [192, 193] and patients with WHO grade II gliomas produced a strong CD8⁺ T cell response after receiving peptide vaccine combined with polyurethrasome (iclc) [194]. Following these encouraging outcomes, VEGF receptor 1 and 2 peptide vaccine was investigated [195], peptide vaccines (ICT-107), autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2, was proposed [196], multiple glioma tumor antigens/glioma angiogenesis-related antigen peptide vaccine was evaluated [197], neoantigen vaccine using multi-epitope, personalized neoantigen vaccination strategies was created [198], and mass cytometry for detecting H3.3K27M-specific vaccine mutant IDH1 vaccine were developed [199, 200]. These vaccines have been tested in newly diagnosed and relapsed GBM diffuse midline glioma respectively, and the results show that they are well tolerated and have good curative effect. However, they all belong to single-center phase I/II clinical trials and need to be further studied.

Nucleic acid vaccine (NAV): Both DNAV and mRNAV are safe and more easily manufactured than SPVs and aim to transmit genetic information encoding tumor antigens (Tas) to the host to generate an anti-cancer immune response [201, 202]. Although NAV is safe and easy to manufacture compared to SPVs, they have so far not been considered a viable alternative to SPVs. Judging from the situation that has been carried out, DNAV for cervical cancer, prostate cancer and breast cancer and mRNAV for melanoma, GBM and prostate cancer have been investigated. A DNA vaccine with a glioma antigen, SOX6 and a vaccine targeting IL13Rα2 have been shown to induce therapeutic anti-tumor immunity in 2008 [203, 204]. Thirteen years later, an immune response of a new DNA-based immunotherapy and increased survival times in different tumor models have also been reported [205]. Between 2021 and 2022, 6 studies used information in the TCGA and/or CGGA databases to screen for suitable tumor-associated or tumor-specific antigen candidates for mRNAV in gliomas but no mRNAVs were synthesized [206, 207, 208, 209, 210, 211]. Therefore, the use of mRNAV as a specific prophylactic vaccine for clinical trials still appears to be distant or not yet feasible at present.

7.4Oncolytic virus therapy

Oncolytic viruses (OVs) can replicate in cancer cells but not in normal cells, leading to death of the tumor cells. Oncolytic viruses therapy (OVT) uses intratumoral delivery of virus to TME for treatment, or causes direct cytotoxicity through viral infection and replication [212, 213]. The treatment induces immunogenic cell death (ICD) in infected tumor cells when destruction of tumor cells by OVT releases antigens into the TME, recruiting and activating local dendritic cells and specific T cells [213]. The research on oncolytic virus has never ceased. Earlier regimens involving the HSV1-tk gene with the antiviral drug acyclovir [212, 214] suffered from poor vector delivery and poor efficacy. However, HSV1G207, developed later, has been shown to be safe and effective in clinical trials. The advantage is that it allows conditional replication in tumor cells while preventing infection of normal cells [215], phase I clinical trials have been conducted, whether alone or in combination with radiotherapy GBM is effective and safe [216, 217, 218]. Furthermore, the new drug, HSV-rQnestin34.5v.2, is currently undergoing clinical trials, and it has demonstrated low toxicity to human beings [219, 220].

8.Summary and outlook

8.1Plasticity of the GSC niche

The aforementioned GSCs Niche are almost ubiquitous in and around GBM entities, and their function has not been fully demonstrated. The perivascular niche (PVN) is considered to be a complex microenvironment containing endothelial cells plus astrocytes, pericytes, immune cells and other stromal cells that regulate GSC biology [221, 222, 223]. It is not clear how the various cellular components of PVN change GSC behavior, such as proliferation, quiescence, invasive dissemination, homing and chemoradiation resistance. Previous 2D and 3D in vitro cultures and tumor-bearing mouse models have inevitable limitations, and bionic models have received great attention and shown a bright future [224, 225, 226, 227, 228, 229, 230]. However, it seems that there are still many difficulties whether the wish of using bionic model to completely replace clinical cases can be achieved. Single-cell sequencing has been used to detect the interactions between GSCs and immune cells during tumorigenesis [13], analyze the inhibition of CD161 receptor by GBM infiltrating T cells [12], reveal functional heterogeneity of glioma-associated brain macrophages [11], and reveal the role of m6A-modified RNA in the glioblastoma microenvironment [231]. Single cell sequencing can detect the molecules of all single cell components from clinical specimens. In biomimetic models, the cells are often artificially introduced or stocked to mimic the natural environment, ranging from biomimicry to simulation, and even high simulation, eventually forming a realistic landscape resembling clinical GBM. However, such models come with potential risks that are difficult to achieve or replicate in reality.

The dynamic nature of CSCs implies plasticity of GSCs [232], reinforcing the message of our recently published review “GSCs and Their Microenvironments: Docking and Transformation” [233]. In short, GSCs change according to the microenvironment and therapeutic signals.

8.2A cure for GBM

Standard care for GBM only prolongs the patient’s very short lifespan and the prognosis is particularly severe for unresectable GBM [234, 235, 236, 237, 238]. Immunotherapy promises to be less than ideal [239, 240, 241]. Future treatment direction pays more attention to combination strategies. For example, the bispecific antibodies targeting two different antigens has proven to be a valuable approach, [242, 243] but the BBB excludes most macromolecular monoclonal antibodies [244, 245]. Fortunately, novel cyclic peptides that modulate BBB functions have been reported to enhance monoclonal antibody delivery to the brain [244] and focused ultrasound-mediated BBB disruption has been showed to improve the delivery of anti-CD47 monoclonal antibodies [246]. Alternatively, intratumoral administration is very valuable for improving drug distribution and sustained release. For example, PLGA nanoparticles which have been found to enhance the penetration of paclitaxel in brain tissue, including some other implants, can improve the therapeutic effect [247, 248, 249, 250, 251]. In addition, nanoformulation has been used to transform “cold” GBM tumors into “hot” and promote immune cell infiltration [252, 253]. Intranasal administration has also been proposed as a potential delivery method [254, 255]. However, most of the mentioned approaches are still in the preclinical stage, and more research is needed to explore their potential effectiveness and safety for further investigation.

Botanical medicines, such as leaf extract of Terminalia catappa L. inhibited tumor cell migration and invasion in a human GBM PDX [256, 257], artemisia annua had an in vitro anti-cancer effect and resveratrol inhibited the proliferation of dendritic cells induced by human GBM GSCs [258].

In short, there is hope to improve GBM, especially the survival prognosis of rGBM, which is currently in the stage of in vitro or in vivo experiments in animals, and there is still a painstaking research process on when incurable GBM can be turned into a treatable one.

8.3A new model of GBM immunotherapy

GBM heterogeneity of cell composition, gene expression and phenotype means that some experimental models involved in the above preclinical studies are over-simplified, such as spheroids which represent a random aggregations of cells without a tissue-like structure, extracellular matrix or neighboring non-tumor cells. Heterogeneous tumor spheres that better meet the requirements of clinical research are being studied, including heterospheres from co-culture of cancer and stromal cells, producing spheroids containing NK cells [259] or grown in the presence of osteoclasts and probiotics, increased cytotoxicity to CSCs [260]. Moreover, an immunocompetent cancer stem cell model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice was developed and used for tested a genetically engineered oncolytic herpes simplex virus that is armed with interleukin 12 (G47-mIL12). The results showed G47Δ-mIL12 could provide a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system [261].

Organotype tissue sectioning models involve culture of surgically removed tumor tissue, maintaining inter- and intra-tumor heterogeneity and tumor structure [262, 263, 264]. This technique does not involve selective growth of tumor cells may be used for personalized treatments and to evaluate individual sensitivity to invasive and patient-specific effects of anti-invasive drugs [263]. An in vitro brain slice model for targeting of brain metastases of breast cancer has also been constructed [265]. Such a model is expected to contribute to immunotherapy studies of solid tumors, including GBM.

Currently, one of the most cutting-edge areas of research is focused on organoid models. Organoid models have the ability to replicate the structure and function of original organs, and in the long-term, they hold the potential to replace patient-based studies [266, 267]. They have potential for basic cancer research, drug screening and personalized susceptibility studies and may bridge the gap between in vitro and in vivo cancer models [266, 268]. The GBM organoid model, generated by traditional 3D culture, genetic engineering and co-culture, shows promise, preserving the phenotype and 3D TME of the original tumor [269, 270, 271, 272, 273, 274, 275, 276, 277, 278]. These methods can also be used to produce other organoid models of brain tumor such as medulloblastoma and brain metastasis. It has been widely used in basic research and clinical transformation research, especially in immunotherapy research, which has considerable potential. Combining innovative technologies, such as 3D bioprinting and 4D real-time imaging, are likely to produce realistic modeling of brain tumor organoids although structural and genetic fidelity aspects remain unclear [279].

In summary, the path towards transforming incurable GBM into a curable condition has come closer, but there is still a considerable distance to cover. Nevertheless, there is hope as a recent seminar, co-organized by the National Brain Tumor Society and the Parker Institute of Cancer Immunotherapy, has brought together experts who have highlighted potential future directions for GBM therapy [280, 281, 282].

9.Conclusions

Glioma microenvironment, which is remodeled by GSCs, is different from other cancers. In addition to the unique characteristics mentioned above, the heterogeneity of GSCs and TME is the key to be clarified in the future. For example, Driving factors of GSC plasticity and heterogeneity (such as reprogramming transcription factors and epigenetic modifications) has been proved to be related to the induction of immunosuppressive cell states, which may lead to therapeutic opportunities for GSC-intrinsic mechanisms [283]. Another example is the interaction between tumor-associated microglia/macrophages and GSCs in TME [284]. We have only verified that SU3 (GSCs) can trigger the malignant transformation of macrophages into cancer cells [285]. However, if we can elucidate the molecular mechanisms underlying this transformation, we may be able to manipulate the related molecules and revert the transformed macrophages back to the M1 state, which could potentially inhibit GSCs.

Data availability

No underlying data was collected or produced in this study.

Author contributions

Conception: HQ, WAM, ZWY, WY.

Interpretation or analysis of data: FXF, WJ, THY, YK, ZYD, JDY, CHC, CH, XXT.

Preparation of the manuscript: FXF, WJ, THY, HQ.

Revision for important intellectual content: HQ, WAM, ZWY, WY.

Supervision: HQ, WAM, ZWY, JDY, CHC.

All authors agree to be accountable for the content of the work.

Funding

This work was funded by grants from the Natural Science Foundation of China (No. 81101909; 81172400; 81272793; 30200335;30672164; 30872654; 81302196; 81302180; 82073873; 82072798), the Health Talent Training Project of Gusu (GSWS2020122), the Youth medical talent Foundation of Jiangsu (QNRC2016217), Suzhou Medical, Health Technology Innovation Project (SKY2021028) and Science and technology planning project of Suzhou (SS2019050) and Nanjing health science and technology development project (YKk18106).

Acknowledgments

The authors would like to express their gratitude to EditSprings [https://www.editsprings.cn] for the expert linguistic services provided.

Conflict of interest

The authors declare that they have no competing interests.

References

[1]	D.N. Louis, A. Perry, P. Wesseling, D.J. Brat, I.A. Cree, D. Figarella-Branger, C. Hawkins, H.K. Ng, S.M. Pfister, G. Reifenberger, R. Soffietti, A. von Deimling and D.W. Ellison, The 2021 WHO classification of tumors of the central nervous system: a summary, Neuro Oncol 23: ((2021) ), 1231–1251.
[2]	Y. Zhao, J. Dong, Q. Huang, M. Lou, A. Wang and Q. Lan, Endothelial cell transdifferentiation of human glioma stem progenitor cells in vitro, Brain Res Bull 82: ((2010) ), 308–12.
[3]	H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal and F. Bray, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J Clin 71: ((2021) ), 209–249.
[4]	A.M. Menzies, R.A. Scolyer and G.V. Long, Neoadjuvant Immunotherapy in Melanoma – The New Frontier, Clin Cancer Res 27: ((2021) ), 4133–4135.
[5]	P.A. Ascierto, A.B. Warner, C. Blank, C. Caracò, S. Demaria, J.E. Gershenwald, N.I. Khushalani, G.V. Long, J.J. Luke, J.M. Mehnert, C. Robert, P. Rutkowski, H.A. Tawbi, I. Osman and I. Puzanov, The “Great Debate” at Melanoma Bridge 2021, December 2nd-4th, 2021, J Transl Med 20: ((2022) ), 200.
[6]	W. Wu, J.L. Klockow, M. Zhang, F. Lafortune, E. Chang, L. Jin, Y. Wu and H.E. Daldrup-Link, Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance, Pharmacol Res 171: ((2021) ), 105780.
[7]	R. Abounader and D. Schiff, The blood-brain barrier limits the therapeutic efficacy of antibody-drug conjugates in glioblastoma, Neuro Oncol 23: ((2021) ), 1993–1994.
[8]	M. Hsu, C. Laaker, A. Madrid, M. Herbath, Y.H. Choi, M. Sandor and Z. Fabry, Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate, Nat Immunol 23: ((2022) ), 581–593.
[9]	M. Brady, A. Rahman, A. Combs, C. Venkatraman, R.T. Kasper, C. McQuaid, W.E. Kwok, R.W. Wood and R. Deane, Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging, Fluids Barriers CNS 17: ((2020) ), 71.
[10]	N.H. Mehta, J. Sherbansky, A.R. Kamer, R.O. Carare, T. Butler, H. Rusinek, G.C. Chiang, Y. Li, S. Strauss, L.A. Saint-Louis, N.D. Theise, R.A. Suss, K. Blennow, M. Kaplitt and M.J. de Leon, The brain-nose interface: A potential cerebrospinal fluid clearance site in humans, Front Physiol 12: ((2021) ), 769948.
[11]	N. Ochocka, P. Segit, K.A. Walentynowicz, K. Wojnicki, S. Cyranowski, J. Swatler, J. Mieczkowski and B. Kaminska, Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages, Nat Commun 12: ((2021) ), 1151.
[12]	N.D. Mathewson, O. Ashenberg, I. Tirosh, S. Gritsch, E.M. Perez, S. Marx, L. Jerby-Arnon, R. Chanoch-Myers, T. Hara, A.R. Richman, Y. Ito, J. Pyrdol, M. Friedrich, K. Schumann, M.J. Poitras, P.C. Gokhale, L.N. Gonzalez Castro, M.E. Shore, C.M. Hebert, B. Shaw, H.L. Cahill, M. Drummond, W. Zhang, O. Olawoyin, H. Wakimoto, O. Rozenblatt-Rosen, P.K. Brastianos, X.S. Liu, P.S. Jones, D.P. Cahill, M.P. Frosch, D.N. Louis, G.J. Freeman, K.L. Ligon, A. Marson, E.A. Chiocca, D.A. Reardon, A. Regev, M.L. Suvà and K.W. Wucherpfennig, Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis, Cell 184: ((2021) ), 1281–1298e26..
[13]	Y. Zhai, G. Li, R. Li, Y. Chang, Y. Feng, D. Wang, F. Wu and W. Zhang, Single-cell RNA-sequencing shift in the interaction pattern between glioma stem cells and immune cells during tumorigenesis, Front Immunol 11: ((2020) ), 581209.
[14]	Z. Yang, Z. Chen, Y. Wang, Z. Wang, D. Zhang, X. Yue, Y. Zheng, L. Li, E. Bian and B. Zhao, A novel defined pyroptosis-related gene signature for predicting prognosis and treatment of glioma, Front Oncol 12: ((2022) ), 717926.
[15]	K. Yang, Z. Wu, H. Zhang, N. Zhang, W. Wu, Z. Wang, Z. Dai, X. Zhang, L. Zhang, Y. Peng, W. Ye, W. Zeng, Z. Liu and Q. Cheng, Glioma targeted therapy: insight into future of molecular approaches, Mol Cancer 21: ((2022) ), 39.
[16]	L. Li and R.A. Jensen, Understanding and overcoming immunosuppression shaped by cancer stem cells, Cancer Res 83: ((2023) ), 2096–2104.
[17]	A. Miranda, P.T. Hamilton, A.W. Zhang, S. Pattnaik, E. Becht, A. Mezheyeuski, J. Bruun, P. Micke, A. de Reynies and B.H. Nelson, Cancer stemness, intratumoral heterogeneity, and immune response across cancers, Proc Natl Acad Sci USA 116: ((2019) ), 9020–9029.
[18]	K.E. de Visser and J.A. Joyce, The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth, Cancer Cell 41: ((2023) ), 374–403.
[19]	T. Xie, J.W. Ma, B. Liu, J. Dong and Q. Huang, [Experimental study of glioma stem cell-mediated immune tolerance in tumor microenvironment], Zhonghua Zhong Liu Za Zhi 39: ((2017) ), 808–813.
[20]	J. Chen, G. Liu, X. Wang, H. Hong, T. Li, L. Li, H. Wang, J. Xie, B. Li, T. Li, D. Lu, Y. Zhang, H. Zhao, C. Yao, K. Wen, T. Li, J. Chen, S. Wu, K. He, W.N. Zhang, J. Zhao, N. Wang, Q. Han, Q. Xia, J. Qi, J. Chen, T. Zhou, J. Man, X.M. Zhang, A.L. Li and X. Pan, Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling, Cell Stem Cell 29: ((2022) ), 1531–1546e7..
[21]	V. Di Nunno, E. Franceschi, A. Tosoni, L. Gatto, S. Bartolini and A.A. Brandes, Tumor-associated microenvironment of adult gliomas: A review, Front Oncol 12: ((2022) ), 891543.
[22]	A.S. Venteicher, I. Tirosh, C. Hebert, K. Yizhak, C. Neftel, M.G. Filbin, V. Hovestadt, L.E. Escalante, M.L. Shaw, C. Rodman, S.M. Gillespie, D. Dionne, C.C. Luo, H. Ravichandran, R. Mylvaganam, C. Mount, M.L. Onozato, B.V. Nahed, H. Wakimoto, W.T. Curry, A.J. Iafrate, M.N. Rivera, M.P. Frosch, T.R. Golub, P.K. Brastianos, G. Getz, A.P. Patel, M. Monje, D.P. Cahill, O. Rozenblatt-Rosen, D.N. Louis, B.E. Bernstein, A. Regev and M.L. Suvà, Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq, Science 355: ((2017) ).
[23]	S.K. Singh, I.D. Clarke, M. Terasaki, V.E. Bonn, C. Hawkins, J. Squire and P.B. Dirks, Identification of a cancer stem cell in human brain tumors, Cancer Res 63: ((2003) ), 5821–8.
[24]	Q.B. Zhang, X.Y. Ji, Q. Huang, J. Dong, Y.D. Zhu and Q. Lan, Differentiation profile of brain tumor stem cells: a comparative study with neural stem cells, Cell Res 16: ((2006) ), 909–15.
[25]	J. Dong, Y. Zhao, Q. Huang, X. Fei, Y. Diao, Y. Shen, H. Xiao, T. Zhang, Q. Lan and X. Gu, Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation, Stem Cell Rev Rep 7: ((2011) ), 141–52.
[26]	J. Feldheim, A.F. Kessler, J.J. Feldheim, E. Schulz, D. Wend, L. Lazaridis, C. Kleinschnitz, M. Glas, R.I. Ernestus, S. Brandner, C.M. Monoranu, M. Löhr and C. Hagemann, Effects of long-term temozolomide treatment on glioblastoma and astrocytoma WHO grade 4 stem-like cells, Int J Mol Sci 23: ((2022) ).
[27]	J.D. Lathia, J. Gallagher, J.T. Myers, M. Li, A. Vasanji, R.E. McLendon, A.B. Hjelmeland, A.Y. Huang and J.N. Rich, Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells, PLoS One 6: ((2011) ), e24807.
[28]	S.K. Singh, I.D. Clarke, T. Hide and P.B. Dirks, Cancer stem cells in nervous system tumors, Oncogene 23: ((2004) ), 7267–73.
[29]	X. Zheng, G. Shen, X. Yang and W. Liu, Most C6 cells are cancer stem cells: evidence from clonal and population analyses, Cancer Res 67: ((2007) ), 3691–7.
[30]	H. Lin, The stem-cell niche theory: lessons from flies, Nat Rev Genet 3: ((2002) ), 931–40.
[31]	L. Li and T. Xie, Stem cell niche: structure and function, Annu Rev Cell Dev Biol 21: ((2005) ), 605–31.
[32]	R. Wang, K. Chadalavada, J. Wilshire, U. Kowalik, K.E. Hovinga, A. Geber, B. Fligelman, M. Leversha, C. Brennan and V. Tabar, Glioblastoma stem-like cells give rise to tumour endothelium, Nature 468: ((2010) ), 829–33.
[33]	L. Ricci-Vitiani, R. Pallini, M. Biffoni, M. Todaro, G. Invernici, T. Cenci, G. Maira, E.A. Parati, G. Stassi, L.M. Larocca and R. De Maria, Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells, Nature 468: ((2010) ), 824–8.
[34]	X.F. Fei, Q.B. Zhang, J. Dong, A.D. Wang, Z.M. Wang and Q. Huang, [Preliminary studies on cell derivation of neovascularization in human glioma and its functional evaluation], Zhonghua Zhong Liu Za Zhi 33: ((2011) ), 726–31.
[35]	V.L. Bautch, Cancer: Tumour stem cells switch sides, Nature 468: ((2010) ), 770–1.
[36]	D.A. Aderetti, V.V.V. Hira, R.J. Molenaar and C.J.F. van Noorden, The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastoma, Biochim Biophys Acta Rev Cancer 1869: ((2018) ), 346–354.
[37]	L.J. Brooks, M.P. Clements, J.J. Burden, D. Kocher, L. Richards, S.C. Devesa, L. Zakka, M. Woodberry, M. Ellis, Z. Jaunmuktane, S. Brandner, G. Morrison, S.M. Pollard, P.B. Dirks, S. Marguerat and S. Parrinello, The white matter is a pro-differentiative niche for glioblastoma, Nat Commun 12: ((2021) ), 2184.
[38]	D. Schiffer, L. Annovazzi, C. Casalone, C. Corona and M. Mellai, Glioblastoma: Microenvironment and Niche Concept, Cancers (Basel) 11: ((2018) ).
[39]	Q. Wang, Z. He, M. Huang, T. Liu, Y. Wang, H. Xu, H. Duan, P. Ma, L. Zhang, S.S. Zamvil, J. Hidalgo, Z. Zhang, D.M. O’Rourke, N. Dahmane, S. Brem, Y. Mou, Y. Gong and Y. Fan, Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α, Nat Commun 9: ((2018) ), 559.
[40]	I.A.W. Ho and W.S.N. Shim, Contribution of the microenvironmental niche to glioblastoma heterogeneity, Biomed Res Int 2017: ((2017) ), 9634172.
[41]	T. Hide, I. Shibahara and T. Kumabe, Novel concept of the border niche: glioblastoma cells use oligodendrocytes progenitor cells (GAOs) and microglia to acquire stem cell-like features, Brain Tumor Pathol 36: ((2019) ), 63–73.
[42]	E. Jung, M. Osswald, M. Ratliff, H. Dogan, R. Xie, S. Weil, D.C. Hoffmann, F.T. Kurz, T. Kessler, S. Heiland, A. von Deimling, F. Sahm, W. Wick and F. Winkler, Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma, Nat Commun 12: ((2021) ), 1014.
[43]	T. Taga and K. Tabu, Glioma progression and recurrence involving maintenance and expansion strategies of glioma stem cells by organizing self-advantageous niche microenvironments, Inflamm Regen 40: ((2020) ), 33.
[44]	M. Guilliams, G.R. Thierry, J. Bonnardel and M. Bajenoff, Establishment and maintenance of the macrophage niche, Immunity 52: ((2020) ), 434–451.
[45]	Y. Pan, Y. Yu, X. Wang and T. Zhang, Tumor-associated macrophages in tumor immunity, Front Immunol 11: ((2020) ), 583084.
[46]	L.J. Wang, Y. Xue and Y. Lou, Tumor-associated macrophages related signature in glioma, Aging (Albany NY) 14: ((2022) ), 2720–2735.
[47]	M. Lim, Y. Xia, C. Bettegowda and M. Weller, Current state of immunotherapy for glioblastoma, Nat Rev Clin Oncol 15: ((2018) ), 422–442.
[48]	J. Larkin, F.S. Hodi and J.D. Wolchok, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N Engl J Med 373: ((2015) ), 1270–1.
[49]	M. Weller, N. Butowski, D.D. Tran, L.D. Recht, M. Lim, H. Hirte, L. Ashby, L. Mechtler, S.A. Goldlust, F. Iwamoto, J. Drappatz, D.M. O’Rourke, M. Wong, M.G. Hamilton, G. Finocchiaro, J. Perry, W. Wick, J. Green, Y. He, C.D. Turner, M.J. Yellin, T. Keler, T.A. Davis, R. Stupp and J.H. Sampson, Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial, Lancet Oncol 18: ((2017) ), 1373–1385.
[50]	A. Omuro, G. Vlahovic, M. Lim, S. Sahebjam, J. Baehring, T. Cloughesy, A. Voloschin, S.H. Ramkissoon, K.L. Ligon, R. Latek, R. Zwirtes, L. Strauss, P. Paliwal, C.T. Harbison, D.A. Reardon and J.H. Sampson, Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143, Neuro Oncol 20: ((2018) ), 674–686.
[51]	S.R. Punekar and J.S. Weber, Intratumoral therapy to make a “Cold” tumor “Hot”: The jury is still out, Clin Cancer Res 28: ((2022) ), 5007–5009.
[52]	V. Lemaire, D. Bassen, M. Reed, R. Song, S. Khalili, Y.T.K. Lien, L. Huang, A.P. Singh, S. Stamatelos, D. Bottino and F. Hua, From cold to hot: Changing perceptions and future opportunities for quantitative systems pharmacology modeling in cancer immunotherapy, Clin Pharmacol Ther 113: ((2023) ), 963–972.
[53]	C.M. Jackson, J. Choi and M. Lim, Mechanisms of immunotherapy resistance: lessons from glioblastoma, Nat Immunol 20: ((2019) ), 1100–1109.
[54]	J.S. O’Donnell, M.W.L. Teng and M.J. Smyth, Cancer immunoediting and resistance to T cell-based immunotherapy, Nat Rev Clin Oncol 16: ((2019) ), 151–167.
[55]	A. Memarnejadian, C.E. Meilleur, C.R. Shaler, K. Khazaie, J.R. Bennink, T.D. Schell and S.M.M. Haeryfar, PD-1 blockade promotes epitope spreading in anticancer CD8(+) T Cell responses by preventing fratricidal death of subdominant clones to relieve immunodomination, J Immunol 199: ((2017) ), 3348-v3359.
[56]	D. Mathios, J.E. Kim, A. Mangraviti, J. Phallen, C.K. Park, C.M. Jackson, T. Garzon-Muvdi, E. Kim, D. Theodros, M. Polanczyk, A.M. Martin, I. Suk, X. Ye, B. Tyler, C. Bettegowda, H. Brem, D.M. Pardoll and M. Lim, Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM, Sci Transl Med 8: ((2016) ), 370ra180.
[57]	A.L. Hung, R. Maxwell, D. Theodros, Z. Belcaid, D. Mathios, A.S. Luksik, E. Kim, A. Wu, Y. Xia, T. Garzon-Muvdi, C. Jackson, X. Ye, B. Tyler, M. Selby, A. Korman, B. Barnhart, S.M. Park, J.I. Youn, T. Chowdhury, C.K. Park, H. Brem, D.M. Pardoll and M. Lim, TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM, Oncoimmunology 7: ((2018) ), e1466769.
[58]	J.E. Kim, M.A. Patel, A. Mangraviti, E.S. Kim, D. Theodros, E. Velarde, A. Liu, E.W. Sankey, A. Tam, H. Xu, D. Mathios, C.M. Jackson, S. Harris-Bookman, T. Garzon-Muvdi, M. Sheu, A.M. Martin, B.M. Tyler, P.T. Tran, X. Ye, A. Olivi, J.M. Taube, P.C. Burger, C.G. Drake, H. Brem, D.M. Pardoll and M. Lim, Combination therapy with anti-PD-1, Anti-TIM-3, and focal radiation results in regression of murine gliomas, Clin Cancer Res 23: ((2017) ), 124–136.
[59]	J. Zeng, A.P. See, J. Phallen, C.M. Jackson, Z. Belcaid, J. Ruzevick, N. Durham, C. Meyer, T.J. Harris, E. Albesiano, G. Pradilla, E. Ford, J. Wong, H.J. Hammers, D. Mathios, B. Tyler, H. Brem, P.T. Tran, D. Pardoll, C.G. Drake and M. Lim, Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas, Int J Radiat Oncol Biol Phys 86: ((2013) ), 343–9.
[60]	A. Wu, R. Maxwell, Y. Xia, P. Cardarelli, M. Oyasu, Z. Belcaid, E. Kim, A. Hung, A.S. Luksik, T. Garzon-Muvdi, C.M. Jackson, D. Mathios, D. Theodros, J. Cogswell, H. Brem, D.M. Pardoll and M. Lim, Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment, J Neurooncol 143: ((2019) ), 241–249.
[61]	R. Medikonda, G. Dunn, M. Rahman, P. Fecci and M. Lim, A review of glioblastoma immunotherapy, J Neurooncol 151: ((2021) ), 41–53.
[62]	C.M. Jackson and M. Lim, Immunotherapy for glioblastoma: playing chess, not checkers, Clin Cancer Res 24: ((2018) ), 4059–4061.
[63]	W. Xiong, C. Li, G. Kong, B. Wan, S. Wang and J. Fan, Glioblastoma: two immune subtypes under the surface of the cold tumor, Aging (Albany NY) 14: ((2022) ), 4357–4375.
[64]	C. Blériot, S. Chakarov and F. Ginhoux, Determinants of resident tissue macrophage identity and function, Immunity 52: ((2020) ), 957–970.
[65]	C.D. Mills, K. Kincaid, J.M. Alt, M.J. Heilman and A.M. Hill, Pillars Article: M-1/M-2 Macrophages and the Th1/Th2 Paradigm, J Immunol 164: ((2000) ) : 6166–6173; J Immunol 199: ((2017) ), 2194–2201.
[66]	K. Beccaria, M. Canney, G. Bouchoux, C. Desseaux, J. Grill, A.B. Heimberger and A. Carpentier, Ultrasound-induced blood-brain barrier disruption for the treatment of gliomas and other primary CNS tumors, Cancer Lett 479: ((2020) ), 13–22.
[67]	A. Sabbagh, K. Beccaria, X. Ling, A. Marisetty, M. Ott, H. Caruso, E. Barton, L.Y. Kong, D. Fang, K. Latha, D.Y. Zhang, J. Wei, J. DeGroot, M.A. Curran, G. Rao, J. Hu, C. Desseaux, G. Bouchoux, M. Canney, A. Carpentier and A.B. Heimberger, Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models, Clin Cancer Res 27: ((2021) ), 4325–4337.
[68]	C. Kim, M. Lim, G.F. Woodworth and C.D. Arvanitis, The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors, J Neurooncol 157: ((2022) ), 221–236.
[69]	M. Toriello, V. González-Quintanilla and J. Pascual, The glymphatic system and its involvement in disorders of the nervous system, Med Clin (Barc) 156: ((2021) ), 339–343.
[70]	G. Yankova, O. Bogomyakova and A. Tulupov, The glymphatic system and meningeal lymphatics of the brain: new understanding of brain clearance, Rev Neurosci 32: ((2021) ), 693–705.
[71]	S. Naganawa and T. Taoka, The glymphatic system: A review of the challenges in visualizing its structure and function with MR imaging, Magn Reson Med Sci 21: ((2022) ), 182–194.
[72]	K. Bene, L. Halasz and L. Nagy, Transcriptional repression shapes the identity and function of tissue macrophages, FEBS Open Bio 11: ((2021) ), 3218–3229.
[73]	Y. Lavin, D. Winter, R. Blecher-Gonen, E. David, H. Keren-Shaul, M. Merad, S. Jung and I. Amit, Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment, Cell 159: ((2014) ), 1312–26.
[74]	A. Buttgereit, I. Lelios, X. Yu, M. Vrohlings, N.R. Krakoski, E.L. Gautier, R. Nishinakamura, B. Becher and M. Greter, Sall1 is a transcriptional regulator defining microglia identity and function, Nat Immunol 17: ((2016) ), 1397–1406.
[75]	C. Minten, R. Terry, C. Deffrasnes, N.J. King and I.L. Campbell, IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS, PLoS One 7: ((2012) ), e49851.
[76]	S. Chen, J. Yang, Y. Wei and X. Wei, Epigenetic regulation of macrophages: from homeostasis maintenance to host defense, Cell Mol Immunol 17: ((2020) ), 36–49.
[77]	N.A. Thornberry, H.G. Bull, J.R. Calaycay, K.T. Chapman, A.D. Howard, M.J. Kostura, D.K. Miller, S.M. Molineaux, J.R. Weidner, J. Aunins et al., A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes, Nature 356: ((1992) ), 768–74.
[78]	J. Shi, Y. Zhao, K. Wang, X. Shi, Y. Wang, H. Huang, Y. Zhuang, T. Cai, F. Wang and F. Shao, Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death, Nature 526: ((2015) ), 660–5.
[79]	N. Kayagaki, I.B. Stowe, B.L. Lee, K. O’Rourke, K. Anderson, S. Warming, T. Cuellar, B. Haley, M. Roose-Girma, Q.T. Phung, P.S. Liu, J.R. Lill, H. Li, J. Wu, S. Kummerfeld, J. Zhang, W.P. Lee, S.J. Snipas, G.S. Salvesen, L.X. Morris, L. Fitzgerald, Y. Zhang, E.M. Bertram, C.C. Goodnow and V.M. Dixit, Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling, Nature 526: ((2015) ), 666–71.
[80]	X. Liu, Z. Zhang, J. Ruan, Y. Pan, V.G. Magupalli, H. Wu and J. Lieberman, Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores, Nature 535: ((2016) ), 153–8.
[81]	J. Shi, W. Gao and F. Shao, Pyroptosis: Gasdermin-mediated programmed necrotic cell death, Trends Biochem Sci 42: ((2017) ), 245–254.
[82]	E.A. Miao, J.V. Rajan and A. Aderem, Caspase-1-induced pyroptotic cell death, Immunol Rev 243: ((2011) ), 206–14.
[83]	S.B. Kovacs and E.A. Miao, Gasdermins: Effectors of pyroptosis, Trends Cell Biol 27: ((2017) ), 673–684.
[84]	Y. Wang, B. Yin, D. Li, G. Wang, X. Han and X. Sun, GSDME mediates caspase-3-dependent pyroptosis in gastric cancer, Biochem Biophys Res Commun 495: ((2018) ), 1418–1425.
[85]	Y.Y. Wang, X.L. Liu and R. Zhao, Induction of pyroptosis and its implications in cancer management, Front Oncol 9: ((2019) ), 971.
[86]	J. Yu, S. Li, J. Qi, Z. Chen, Y. Wu, J. Guo, K. Wang, X. Sun and J. Zheng, Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells, Cell Death Dis 10: ((2019) ), 193.
[87]	Y. Fang, S. Tian, Y. Pan, W. Li, Q. Wang, Y. Tang, T. Yu, X. Wu, Y. Shi, P. Ma and Y. Shu, Pyroptosis: A new frontier in cancer, Biomed Pharmacother 121: ((2020) ), 109595.
[88]	J.K. Rathkey, J. Zhao, Z. Liu, Y. Chen, J. Yang, H.C. Kondolf, B.L. Benson, S.M. Chirieleison, A.Y. Huang, G.R. Dubyak, T.S. Xiao, X. Li and D.W. Abbott, Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis, Sci Immunol 3: ((2018) ).
[89]	C.L. Evavold, J. Ruan, Y. Tan, S. Xia, H. Wu and J.C. Kagan, The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages, Immunity 48: ((2018) ), 35–44e6..
[90]	F. Humphries, L. Shmuel-Galia, N. Ketelut-Carneiro, S. Li, B. Wang, V.V. Nemmara, R. Wilson, Z. Jiang, F. Khalighinejad, K. Muneeruddin, S.A. Shaffer, R. Dutta, C. Ionete, S. Pesiridis, S. Yang, P.R. Thompson and K.A. Fitzgerald, Succination inactivates gasdermin D and blocks pyroptosis, Science 369: ((2020) ), 1633–1637.
[91]	J.J. Hu, X. Liu, S. Xia, Z. Zhang, Y. Zhang, J. Zhao, J. Ruan, X. Luo, X. Lou, Y. Bai, J. Wang, L.R. Hollingsworth, V.G. Magupalli, L. Zhao, H.R. Luo, J. Kim, J. Lieberman and H. Wu, FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation, Nat Immunol 21: ((2020) ), 736–745.
[92]	C.L. Evavold, I. Hafner-Bratkovič, P. Devant, J.M. D’Andrea, E.M. Ngwa, E. Boršić, J.G. Doench, M.W. LaFleur, A.H. Sharpe, J.R. Thiagarajah and J.C. Kagan, Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway, Cell 184: ((2021) ), 4495–4511e19..
[93]	X.X. Liao, Y.Z. Dai, Y.Z. Zhao and K. Nie, Gasdermin E: A prospective target for therapy of diseases, Front Pharmacol 13: ((2022) ), 855828.
[94]	J. Zou, Y. Zheng, Y. Huang, D. Tang, R. Kang and R. Chen, The versatile gasdermin family: Their function and roles in diseases, Front Immunol 12: ((2021) ), 751533.
[95]	B. Chao, F. Jiang, H. Bai, P. Meng, L. Wang and F. Wang, Predicting the prognosis of glioma by pyroptosis-related signature, J Cell Mol Med 26: ((2022) ), 133–143.
[96]	P. Chen, Y. Li, N. Li, L. Shen and Z. Li, Comprehensive analysis of pyroptosis-associated in molecular classification, immunity and prognostic of glioma, Front Genet 12: ((2021) ), 781538.
[97]	Y. Zhang, F. Xi, Q. Yu, W. Lou, Z. Zeng, N. Su, J. Gao, S. Duan, Y. Deng, S. Guo, S. Lai, X. Tang and J. Zhang, Identification of a novel pyroptosis-related gene signature correlated with the prognosis of diffuse glioma patients, Ann Transl Med 9: ((2021) ), 1766.
[98]	M. Zhang, Y. Cheng, Z. Xue, Q. Sun and J. Zhang, A novel pyroptosis-related gene signature predicts the prognosis of glioma through immune infiltration, BMC Cancer 21: ((2021) ), 1311.
[99]	X. Niu, R. Cheng, Y. Wang, J. Chen, C. Wang and H. Ji, Development of a prognostic model of glioma based on pyroptosis-related genes, World Neurosurg 158: ((2022) ), e929–e945.
[100]	L. Gao, Z. Jiang, Y. Han, Y. Li and X. Yang, Regulation of Pyroptosis by ncRNA: A Novel Research Direction, Front Cell Dev Biol 10: ((2022) ), 840576.
[101]	Y. Liu, H. Wu, J. Jing, H. Li, S. Dong and Q. Meng, Downregulation of hsa_circ_0001836 induces pyroptosis cell death in glioma cells via epigenetically upregulating NLRP1, Front Oncol 11: ((2021) ), 622727.
[102]	T. Jin, M. Liu, Y. Liu, Y. Li, Z. Xu, H. He, J. Liu, Y. Zhang and Y. Ke, Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis, Front Oncol 10: ((2020) ), 170.
[103]	L. Chen, C. Wang, H. Sun, J. Wang, Y. Liang, Y. Wang and G. Wong, The bioinformatics toolbox for circRNA discovery and analysis, Brief Bioinform 22: ((2021) ), 1706–1728.
[104]	G. Liang, Y. Ling, M. Mehrpour, P.E. Saw, Z. Liu, W. Tan, Z. Tian, W. Zhong, W. Lin, Q. Luo, Q. Lin, Q. Li, Y. Zhou, A. Hamai, P. Codogno, J. Li, E. Song and C. Gong, Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression, Mol Cancer 19: ((2020) ), 65.
[105]	Z. Liu, Q. Wang, X. Wang, Z. Xu, X. Wei and J. Li, Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5, Cell Death Discov 6: ((2020) ), 72.
[106]	J. Guarnerio, Y. Zhang, G. Cheloni, R. Panella, J. Mae Katon, M. Simpson, A. Matsumoto, A. Papa, C. Loretelli, A. Petri, S. Kauppinen, C. Garbutt, G.P. Nielsen, V. Deshpande, M. Castillo-Martin, C. Cordon-Cardo, S. Dimitrios, J.G. Clohessy, M. Batish and P.P. Pandolfi, Intragenic antagonistic roles of protein and circRNA in tumorigenesis, Cell Res 29: ((2019) ), 628–640.
[107]	T. Yu, Y. Wang, Y. Fan, N. Fang, T. Wang, T. Xu and Y. Shu, CircRNAs in cancer metabolism: a review, J Hematol Oncol 12: ((2019) ), 90.
[108]	J. Liu, X. Dou, C. Chen, C. Chen, C. Liu, M.M. Xu, S. Zhao, B. Shen, Y. Gao, D. Han and C. He, N (6)-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription, Science 367: ((2020) ), 580–586.
[109]	J. Li, F. Cao, H.L. Yin, Z.J. Huang, Z.T. Lin, N. Mao, B. Sun and G. Wang, Ferroptosis: past, present and future, Cell Death Dis 11: ((2020) ), 88.
[110]	R.J. Wan, W. Peng, Q.X. Xia, H.H. Zhou and X.Y. Mao, Ferroptosis-related gene signature predicts prognosis and immunotherapy in glioma, CNS Neurosci Ther 27: ((2021) ), 973–986.
[111]	J. Zheng, Z. Zhou, Y. Qiu, M. Wang, H. Yu, Z. Wu, X. Wang and X. Jiang, A prognostic ferroptosis-related lncRNAs signature associated with immune landscape and radiotherapy response in glioma, Front Cell Dev Biol 9: ((2021) ), 675555.
[112]	X. Zhu, Y. Zhou, Y. Ou, Z. Cheng, D. Han, Z. Chu and S. Pan, Characterization of ferroptosis signature to evaluate the predict prognosis and immunotherapy in glioblastoma, Aging (Albany NY) 13: ((2021) ), 17655–17672.
[113]	L. Sun, B. Li, B. Wang, J. Li and J. Li, Construction of a risk model to predict the prognosis and immunotherapy of low-grade glioma ground on 7 ferroptosis-related genes, Int J Gen Med 15: ((2022) ), 4697–4716.
[114]	D. Tang, R. Kang, T.V. Berghe, P. Vandenabeele and G. Kroemer, The molecular machinery of regulated cell death, Cell Res 29: ((2019) ), 347–364.
[115]	W. Wang, M. Green, J.E. Choi, M. Gijón, P.D. Kennedy, J.K. Johnson, P. Liao, X. Lang, I. Kryczek, A. Sell, H. Xia, J. Zhou, G. Li, J. Li, W. Li, S. Wei, L. Vatan, H. Zhang, W. Szeliga, W. Gu, R. Liu, T.S. Lawrence, C. Lamb, Y. Tanno, M. Cieslik, E. Stone, G. Georgiou, T.A. Chan, A. Chinnaiyan and W. Zou, CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy, Nature 569: ((2019) ), 270–274.
[116]	C. Wan, Y. Sun, Y. Tian, L. Lu, X. Dai, J. Meng, J. Huang, Q. He, B. Wu, Z. Zhang, K. Jiang, D. Hu, G. Wu, J.F. Lovell, H. Jin and K. Yang, Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming, Sci Adv 6: ((2020) ), eaay9789.
[117]	I. Efimova, E. Catanzaro, L. Van der Meeren, V.D. Turubanova, H. Hammad, T.A. Mishchenko, M.V. Vedunova, C. Fimognari, C. Bachert, F. Coppieters, S. Lefever, A.G. Skirtach, O. Krysko and D.V. Krysko, Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity, J Immunother Cancer 8: ((2020) ).
[118]	D. Xiao, Y. Zhou, X. Wang, H. Zhao, C. Nie and X. Jiang, A ferroptosis-related prognostic risk score model to predict clinical significance and immunogenic characteristics in glioblastoma multiforme, Oxid Med Cell Longev 2021: ((2021) ), 9107857.
[119]	A.O. Mitre, A.I. Florian, A. Buruiana, A. Boer, I. Moldovan, O. Soritau, S.I. Florian and S. Susman, Ferroptosis involvement in glioblastoma treatment, Medicina (Kaunas) 58: ((2022) ).
[120]	J. Van Loenhout, L. Freire Boullosa, D. Quatannens, J. De Waele, C. Merlin, H. Lambrechts, H.W. Lau, C. Hermans, A. Lin, F. Lardon, M. Peeters, A. Bogaerts, E. Smits and C. Deben, Auranofin and cold atmospheric plasma synergize to trigger distinct cell death mechanisms and immunogenic responses in glioblastoma, Cells 10: ((2021) ).
[121]	Q. Song, S. Peng, Z. Sun, X. Heng and X. Zhu, Temozolomide drives ferroptosis via a DMT1-dependent pathway in glioblastoma cells, Yonsei Med J 62: ((2021) ), 843–849.
[122]	C. Qiu, X. Zhang, B. Huang, S. Wang, W. Zhou, C. Li, X. Li, J. Wang and N. Yang, Disulfiram, a ferroptosis inducer, triggers lysosomal membrane permeabilization by Up-Regulating ROS in glioblastoma, Onco Targets Ther 13: ((2020) ), 10631–10640.
[123]	I.C. Su, Y.K. Su, S.A. Setiawan, V.K. Yadav, I.H. Fong, C.T. Yeh, C.M. Lin and H.W. Liu, NADPH Oxidase Subunit CYBB Confers Chemotherapy and Ferroptosis Resistance in Mesenchymal Glioblastoma via Nrf2/SOD2 Modulation, Int J Mol Sci 24: ((2023) ).
[124]	K. Liu, L. Jiang, Y. Shi, B. Liu, Y. He, Q. Shen, X. Jiang, Z. Nie, J. Pu, C. Yang and Y. Chen, Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation, Cell Death Differ 29: ((2022) ), 1834–1849.
[125]	J. Yue, R. Huang, Z. Lan, B. Xiao and Z. Luo, Abnormal glycosylation in glioma: related changes in biology, biomarkers and targeted therapy, Biomark Res 11: ((2023) ), 54.
[126]	Y. Qi, W. Lv, X. Liu, Q. Wang, B. Xing, Q. Jiang, Z. Wang, Y. Huang, K. Shu and T. Lei, Comprehensive analysis identified glycosyltransferase signature to predict glioma prognosis and TAM phenotype, Biomed Res Int 2023: ((2023) ), 6082635.
[127]	X. Wu, H. Wang, S. Li, H. Luo and F. Liu, Mining glycosylation-related prognostic lncRNAs and constructing a prognostic model for overall survival prediction in glioma: A study based on bioinformatics analysis, Medicine (Baltimore) 102: ((2023) ), e33569.
[128]	S.K. Natarajan and S. Venneti, Glioblastoma stem cell HISTArionics, Cell Stem Cell 29: ((2022) ), 1509–1510.
[129]	C. Cencioni, F. Scagnoli, F. Spallotta, S. Nasi and B. Illi, The “superoncogene” myc at the crossroad between metabolism and gene expression in glioblastoma multiforme, Int J Mol Sci 24: ((2023) ).
[130]	A. Aspelund, S. Antila, S.T. Proulx, T.V. Karlsen, S. Karaman, M. Detmar, H. Wiig and K. Alitalo, A dural Iymphatic vascular system that drains brain interstitial fluid and macromolecules, J Exp Med 212: ((2015) ), 991–9.
[131]	A. Louveau, I. Smirnov, T.J. Keyes, J.D. Eccles, S.J. Rouhani, J.D. Peske, N.C. Derecki, D. Castle, J.W. Mandell, K.S. Lee, T.H. Harris and J. Kipnis, Structural and functional features of central nervous system lymphatic vessels, Nature 523: ((2015) ), 337–41.
[132]	J.H. Ahn, H. Cho, J.H. Kim, S.H. Kim, J.S. Ham, I. Park, S.H. Suh, S.P. Hong, J.H. Song, Y.K. Hong, Y. Jeong, S.H. Park and G.Y. Koh, Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid, Nature 572: ((2019) ), 62–66.
[133]	M. Hsu, A. Rayasam, J.A. Kijak, Y.H. Choi, J.S. Harding, S.A. Marcus, W.J. Karpus, M. Sandor and Z. Fabry, Neuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells, Nat Commun 10: ((2019) ), 229.
[134]	X. Hu, Q. Deng, L. Ma, Q. Li, Y. Chen, Y. Liao, F. Zhou, C. Zhang, L. Shao, J. Feng, T. He, W. Ning, Y. Kong, Y. Huo, A. He, B. Liu, J. Zhang, R. Adams, Y. He, F. Tang, X. Bian and J. Luo, Meningeal lymphatic vessels regulate brain tumor drainage and immunity, Cell Res 30: ((2020) ), 229–243.
[135]	E. Song, T. Mao, H. Dong, L.S.B. Boisserand, S. Antila, M. Bosenberg, K. Alitalo, J.L. Thomas and A. Iwasaki, VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours, Nature 577: ((2020) ), 689–694.
[136]	S.T. Proulx, Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics, Cell Mol Life Sci 78: ((2021) ), 2429–2457.
[137]	Q. Ma, F. Schlegel, S.B. Bachmann, H. Schneider, Y. Decker, M. Rudin, M. Weller, S.T. Proulx and M. Detmar, Lymphatic outflow of cerebrospinal fluid is reduced in glioma, Sci Rep 9: ((2019) ), 14815.
[138]	E.S. Norton, L.A. Whaley, M.J. Ulloa-Navas, P. García-Tárraga, K.M. Meneses, M. Lara-Velazquez, N. Zarco, A. Carrano, A. Quiñones-Hinojosa, J.M. García-Verdugo and H. Guerrero-Cázares, Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone, Fluids Barriers CNS 19: ((2022) ), 58.
[139]	T. McGranahan, K.E. Therkelsen, S. Ahmad and S. Nagpal, Current state of immunotherapy for treatment of glioblastoma, Curr Treat Options Oncol 20: ((2019) ), 24.
[140]	N. Zhang, L. Wei, M. Ye, C. Kang and H. You, Treatment progress of immune checkpoint blockade therapy for glioblastoma, Front Immunol 11: ((2020) ), 592612.
[141]	I. Bryukhovetskiy, Cell-based immunotherapy of glioblastoma multiforme, Oncol Lett 23: ((2022) ), 133.
[142]	S. Rohit Reddy, A. Llukmani, A. Hashim, D.R. Haddad, D.S. Patel, F. Ahmad, M. Abu Sneineh and D.K. Gordon, The role of chimeric antigen Receptor-T Cell therapy in the treatment of hematological malignancies: advantages, trials, and tribulations, and the road ahead, Cureus 13: ((2021) ), e13552.
[143]	C.T. Petersen and G. Krenciute, Next generation CAR T cells for the immunotherapy of High-Grade glioma, Front Oncol 9: ((2019) ), 69.
[144]	H.J. Yoo and B.N. Harapan, Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology, Immunol Res 69: ((2021) ), 471–486.
[145]	B. Yuan, G. Wang, X. Tang, A. Tong and L. Zhou, Immunotherapy of glioblastoma: Recent advances and future prospects, Hum Vaccin Immunother 18: ((2022) ), 2055417.
[146]	A. Mintz, D.M. Gibo, B. Slagle-Webb, N.D. Christensen and W. Debinski, IL-13Ralpha2 is a glioma-restricted receptor for interleukin-13, Neoplasia 4: ((2002) ), 388–99.
[147]	S. Sengupta, B. Thaci, A.C. Crawford and P. Sampath, Interleukin-13 receptor alpha 2-targeted glioblastoma immunotherapy, Biomed Res Int 2014: ((2014) ), 952128.
[148]	M. Tu, W. Wange, L. Cai, P. Zhu, Z. Gao and W. Zheng, IL-13 receptor α2 stimulates human glioma cell growth and metastasis through the Src/PI3K/Akt/mTOR signaling pathway, Tumour Biol 37: ((2016) ), 14701–14709.
[149]	C.E. Brown, C.D. Warden, R. Starr, X. Deng, B. Badie, Y.C. Yuan, S.J. Forman and M.E. Barish, Glioma IL13Rα2 is associated with mesenchymal signature gene expression and poor patient prognosis, PLoS One 8: ((2013) ), e77769.
[150]	S. Kong, S. Sengupta, B. Tyler, A.J. Bais, Q. Ma, S. Doucette, J. Zhou, A. Sahin, B.S. Carter, H. Brem, R.P. Junghans and P. Sampath, Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells, Clin Cancer Res 18: ((2012) ), 5949–60.
[151]	N. Muhammad, R. Wang, W. Li, Z. Zhang, Y. Chang, Y. Hu, J. Zhao, X. Zheng, Q. Mao and H. Xia, A novel TanCAR targeting IL13Rα2 and EphA2 for enhanced glioblastoma therapy, Mol Ther Oncolytics 24: ((2022) ), 729–741.
[152]	C.J. Shen, Y.X. Yang, E.Q. Han, N. Cao, Y.F. Wang, Y. Wang, Y.Y. Zhao, L.M. Zhao, J. Cui, P. Gupta, A.J. Wong and S.Y. Han, Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma, J Hematol Oncol 6: ((2013) ), 33.
[153]	D.M. O’Rourke, M.P. Nasrallah, A. Desai, J.J. Melenhorst, K. Mansfield, J.J.D. Morrissette, M. Martinez-Lage, S. Brem, E. Maloney, A. Shen, R. Isaacs, S. Mohan, G. Plesa, S.F. Lacey, J.M. Navenot, Z. Zheng, B.L. Levine, H. Okada, C.H. June, J.L. Brogdon and M.V. Maus, A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma, Sci Transl Med 9: ((2017) ).
[154]	A. Sahin, C. Sanchez, S. Bullain, P. Waterman, R. Weissleder and B.S. Carter, Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma, PLoS One 13: ((2018) ), e0199414.
[155]	A. Oprita, S.C. Baloi, G.A. Staicu, O. Alexandru, D.E. Tache, S. Danoiu, E.S. Micu and A.S. Sevastre, Updated Insights on EGFR signaling pathways in glioma, Int J Mol Sci 22: ((2021) ).
[156]	N. Müller, S. Michen, S. Tietze, K. Töpfer, A. Schulte, K. Lamszus, M. Schmitz, G. Schackert, I. Pastan and A. Temme, Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1α-secreting glioblastoma, J Immunother 38: ((2015) ), 197–210.
[157]	K. Töpfer, M. Cartellieri, S. Michen, R. Wiedemuth, N. Müller, D. Lindemann, M. Bachmann, M. Füssel, G. Schackert and A. Temme, DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy, J Immunol 194: ((2015) ), 3201–12.
[158]	J. Han, J. Chu, W. Keung Chan, J. Zhang, Y. Wang, J.B. Cohen, A. Victor, W.H. Meisen, S.H. Kim, P. Grandi, Q.E. Wang, X. He, I. Nakano, E.A. Chiocca, J.C. Glorioso Iii, B. Kaur, M.A. Caligiuri and J. Yu, CAR-Engineered NK cells targeting Wild-Type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells, Sci Rep 5: ((2015) ), 11483.
[159]	K. Schönfeld, C. Sahm, C. Zhang, S. Naundorf, C. Brendel, M. Odendahl, P. Nowakowska, H. Bönig, U. Köhl, S. Kloess, S. Köhler, H. Holtgreve-Grez, A. Jauch, M. Schmidt, R. Schubert, K. Kühlcke, E. Seifried, H.G. Klingemann, M.A. Rieger, T. Tonn, M. Grez and W.S. Wels, Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor, Mol Ther 23: ((2015) ), 330–8.
[160]	A. Jamali, J. Hadjati, Z. Madjd, H.R. Mirzaei, F.B. Thalheimer, S. Agarwal, H. Bonig, E. Ullrich and J. Hartmann, Highly efficient generation of transgenically augmented CAR NK cells overexpressing CXCR4, Front Immunol 11: ((2020) ), 2028.
[161]	G.H. Ran, Y.Q. Lin, L. Tian, T. Zhang, D.M. Yan, J.H. Yu and Y.C. Deng, Natural killer cell homing and trafficking in tissues and tumors: from biology to application, Signal Transduct Target Ther 7: ((2022) ), 205.
[162]	L.Y. Chan, S.A. Dass, G.J. Tye, S.A.M. Imran, W.S. Wan Kamarul Zaman and F. Nordin, CAR-T cells/-NK Cells in Cancer Immunotherapy and the Potential of MSC to Enhance Its Efficacy: A Review, Biomedicines 10: ((2022) ).
[163]	G. Golinelli, G. Grisendi, M. Prapa, M. Bestagno, C. Spano, F. Rossignoli, F. Bambi, I. Sardi, M. Cellini, E.M. Horwitz, A. Feletti, G. Pavesi and M. Dominici, Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors, Cancer Gene Ther 27: ((2020) ), 558–570.
[164]	T.D. Traylor and E.L. Hogan, Gangliosides of human cerebral astrocytomas, J Neurochem 34: ((1980) ), 126–31.
[165]	J.G. Zhang, C.A. Kruse, L. Driggers, N. Hoa, J. Wisoff, J.C. Allen, D. Zagzag, E.W. Newcomb and M.R. Jadus, Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy, J Neurooncol 88: ((2008) ), 65–76.
[166]	N. Ahmed, V.S. Salsman, Y. Kew, D. Shaffer, S. Powell, Y.J. Zhang, R.G. Grossman, H.E. Heslop and S. Gottschalk, HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors, Clin Cancer Res 16: ((2010) ), 474–85.
[167]	N. Ahmed, V. Brawley, M. Hegde, K. Bielamowicz, M. Kalra, D. Landi, C. Robertson, T.L. Gray, O. Diouf, A. Wakefield, A. Ghazi, C. Gerken, Z. Yi, A. Ashoori, M.F. Wu, H. Liu, C. Rooney, G. Dotti, A. Gee, J. Su, Y. Kew, D. Baskin, Y.J. Zhang, P. New, B. Grilley, M. Stojakovic, J. Hicks, S.Z. Powell, M.K. Brenner, H.E. Heslop, R. Grossman, W.S. Wels and S. Gottschalk, HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial, JAMA Oncol 3: ((2017) ), 1094–1101.
[168]	S. Yang, W. Wei and Q. Zhao, B7-H3, a checkpoint molecule, as a target for cancer immunotherapy, Int J Biol Sci 16: ((2020) ), 1767–1773.
[169]	R.G. Majzner, J.L. Theruvath, A. Nellan, S. Heitzeneder, Y. Cui, C.W. Mount, S.P. Rietberg, M.H. Linde, P. Xu, C. Rota, E. Sotillo, L. Labanieh, D.W. Lee, R.J. Orentas, D.S. Dimitrov, Z. Zhu, B.S. Croix, A. Delaidelli, A. Sekunova, E. Bonvini, S.S. Mitra, M.M. Quezado, R. Majeti, M. Monje, P.H.B. Sorensen, J.M. Maris and C.L. Mackall, CAR T cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors, Clin Cancer Res 25: ((2019) ), 2560–2574.
[170]	Z. Zhou, N. Luther, G.M. Ibrahim, C. Hawkins, R. Vibhakar, M.H. Handler and M.M. Souweidane, B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma, J Neurooncol 111: ((2013) ), 257–64.
[171]	X. Tang, S. Zhao, Y. Zhang, Y. Wang, Z. Zhang, M. Yang, Y. Zhu, G. Zhang, G. Guo, A. Tong and L. Zhou, B7-H3 as a novel CAR-T therapeutic target for glioblastoma, Mol Ther Oncolytics 14: ((2019) ), 279–287.
[172]	D. Nehama, N. Di Ianni, S. Musio, H. Du, M. Patané, B. Pollo, G. Finocchiaro, J.J.H. Park, D.E. Dunn, D.S. Edwards, J.S. Damrauer, H. Hudson, S.R. Floyd, S. Ferrone, B. Savoldo, S. Pellegatta and G. Dotti, B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres, EBioMedicine 47: ((2019) ), 33–43.
[173]	L. Miao, J. Zhang, Z. Zhang, S. Wang, F. Tang, M. Teng and Y. Li, A bibliometric and knowledge-map analysis of CAR-T cells from 2009 to 2021, Front Immunol 13: ((2022) ), 840956.
[174]	A. Ghouzlani, S. Kandoussi, M. Tall, K.P. Reddy, S. Rafii and A. Badou, Immune Checkpoint Inhibitors in Human Glioma Microenvironment, Front Immunol 12: ((2021) ), 679425.
[175]	Y. Jiang, M. Chen, H. Nie and Y. Yuan, PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations, Hum Vaccin Immunother 15: ((2019) ), 1111–1122.
[176]	Z. Zhu, H. Zhang, B. Chen, X. Liu, S. Zhang, Z. Zong and M. Gao, PD-L1-Mediated Immunosuppression in Glioblastoma Is Associated With the Infiltration and M2-Polarization of Tumor-Associated Macrophages, Front Immunol 11: ((2020) ), 588552.
[177]	M. Puigdelloses, M. Garcia-Moure, S. Labiano, V. Laspidea, M. Gonzalez-Huarriz, M. Zalacain, L. Marrodan, N. Martinez-Velez, D. De la Nava, I. Ausejo, S. Hervás-Stubbs, G. Herrador, Z. Chen, D. Hambardzumyan, A. Patino Garcia, H. Jiang, C. Gomez-Manzano, J. Fueyo, J. Gállego Pérez-Larraya and M. Alonso, CD137 and PD-L1 targeting with immunovirotherapy induces a potent and durable antitumor immune response in glioblastoma models, J Immunother Cancer 9: ((2021) ).
[178]	J. Niogret, H. Berger, C. Rebe, R. Mary, E. Ballot, C. Truntzer, M. Thibaudin, V. Derangère, C. Hibos, L. Hampe, D. Rageot, T. Accogli, P. Joubert, B. Routy, J. Harker, F. Vegran, F. Ghiringhelli and F. Chalmin, Follicular helper-T cells restore CD8(+)-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy, J Immunother Cancer 9: ((2021) ).
[179]	T.B. Scheffel, N. Grave, P. Vargas, F.M. Diz, L. Rockenbach and F.B. Morrone, Immunosuppression in gliomas via PD-1/PD-L1 axis and adenosine pathway, Front Oncol 10: ((2020) ), 617385.
[180]	I. Raphael, R. Kumar, L.H. McCarl, K. Shoger, L. Wang, P. Sandlesh, C.T. Sneiderman, J. Allen, S. Zhai, M.L. Campagna, A. Foster, T.C. Bruno, S. Agnihotri, B. Hu, B.A. Castro, F.S. Lieberman, A. Broniscer, A.A. Diaz, N.M. Amankulor, D. Rajasundaram, I.F. Pollack and G. Kohanbash, TIGIT and PD-1 Immune checkpoint pathways are associated with patient outcome and anti-tumor immunity in glioblastoma, Front Immunol 12: ((2021) ), 637146.
[181]	S. Zhang, X. Xiao, Y. Wang, T. Song, C. Li, H. Bao, Q. Liu, G. Sun, X. Sun, T. Su, T. Fu, Y. Wang and P. Liang, Developing an immune-related signature for predicting survival rate and the response to immune checkpoint inhibitors in patients with glioma, Front Genet 13: ((2022) ), 899125.
[182]	R. Liu, W. Liang, Q. Hua, L. Wu, X. Wang, Q. Li, F. Zhong, B. Li and Z. Qiu, Fatty acid metabolic signaling pathway alternation predict prognosis of immune checkpoint inhibitors in glioblastoma, Front Immunol 13: ((2022) ), 819515.
[183]	G. Lai, K. Li, J. Deng, H. Liu, B. Xie and X. Zhong, Identification and validation of a gene signature for lower-grade gliomas based on pyroptosis-related genes to predict survival and response to immune checkpoint inhibitors, J Healthc Eng 2022: ((2022) ), 8704127.
[184]	T. Tian, R. Liang, G. Erel-Akbaba, L. Saad, P.J. Obeid, J. Gao, E.A. Chiocca, R. Weissleder and B.A. Tannous, Immune checkpoint inhibition in GBM Primed with radiation by engineered extracellular vesicles, ACS Nano 16: ((2022) ), 1940–1953.
[185]	Y. Yan, S. Zeng, Z. Gong and Z. Xu, Clinical implication of cellular vaccine in glioma: current advances and future prospects, J Exp Clin Cancer Res 39: ((2020) ), 257.
[186]	O. Insug, G. Ku, H.C. Ertl and M. Blaszczyk-Thurin, A dendritic cell vaccine induces protective immunity to intracranial growth of glioma, Anticancer Res 22: ((2002) ), 613–21.
[187]	C.H. Kim, S.J. Woo, J.S. Park, H.S. Kim, M.Y. Park, S.D. Park, Y.K. Hong and T.G. Kim, Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma, Immunology 122: ((2007) ), 615–22.
[188]	B. Ji, Q. Chen, B. Liu, L. Wu, D. Tian, Z. Guo and W. Yi, Glioma stem cell-targeted dendritic cells as a tumor vaccine against malignant glioma, Yonsei Med J 54: ((2013) ), 92–100.
[189]	F. Tian, C. Dou, S. Qi, B. Chen, L. Zhao and X. Wang, Dendritic cell-glioma fusion activates T lymphocytes by elevating cytotoxic efficiency as an antitumor vaccine, Cent Eur J Immunol 39: ((2014) ), 265–70.
[190]	L.M. Liau, K. Ashkan, D.D. Tran, J.L. Campian, J.E. Trusheim, C.S. Cobbs, J.A. Heth, M. Salacz, S. Taylor, S.D. D’Andre, F.M. Iwamoto, E.J. Dropcho, Y.A. Moshel, K.A. Walter, C.P. Pillainayagam, R. Aiken, R. Chaudhary, S.A. Goldlust, D.A. Bota, P. Duic, J. Grewal, H. Elinzano, S.A. Toms, K.O. Lillehei, T. Mikkelsen, T. Walbert, S.R. Abram, A.J. Brenner, S. Brem, M.G. Ewend, S. Khagi, J. Portnow, L.J. Kim, W.G. Loudon, R.C. Thompson, D.E. Avigan, K.L. Fink, F.J. Geoffroy, S. Lindhorst, J. Lutzky, A.E. Sloan, G. Schackert, D. Krex, H.J. Meisel, J. Wu, R.P. Davis, C. Duma, A.B. Etame, D. Mathieu, S. Kesari, D. Piccioni, M. Westphal, D.S. Baskin, P.Z. New, M. Lacroix, S.A. May, T.J. Pluard, V. Tse, R.M. Green, J.L. Villano, M. Pearlman, K. Petrecca, M. Schulder, L.P. Taylor, A.E. Maida, R.M. Prins, T.F. Cloughesy, P. Mulholland and M.L. Bosch, First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma, J Transl Med 16: ((2018) ), 142.
[191]	M.P. Pinho, G.A. Lepski, R. Rehder, N.E. Chauca-Torres, G.C.M. Evangelista, S.F. Teixeira, E.A. Flatow, J.V. de Oliveira, C.S. Fogolin, N. Peres, A. Arévalo, V. Alves, J.A.M. Barbuto and P.C. Bergami-Santos, Near-complete remission of glioblastoma in a patient treated with an allogenic dendritic cell-based vaccine: The role of tumor-specific CD4+T-cell cytokine secretion pattern in predicting response and recurrence, Int J Mol Sci 23: ((2022) ).
[192]	X. Zhu, F. Nishimura, K. Sasaki, M. Fujita, J.E. Dusak, J. Eguchi, W. Fellows-Mayle, W.J. Storkus, P.R. Walker, A.M. Salazar and H. Okada, Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models, J Transl Med 5: ((2007) ), 10.
[193]	R. Ueda, M. Fujita, X. Zhu, K. Sasaki, E.R. Kastenhuber, G. Kohanbash, H.A. McDonald, J. Harper, S. Lonning and H. Okada, Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines, Clin Cancer Res 15: ((2009) ), 6551–9.
[194]	H. Okada, L.H. Butterfield, R.L. Hamilton, A. Hoji, M. Sakaki, B.J. Ahn, G. Kohanbash, J. Drappatz, J. Engh, N. Amankulor, M.O. Lively, M.D. Chan, A.M. Salazar, E.G. Shaw, D.M. Potter and F.S. Lieberman, Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC, Clin Cancer Res 21: ((2015) ), 286–94.
[195]	S. Shibao, R. Ueda, K. Saito, R. Kikuchi, H. Nagashima, A. Kojima, H. Kagami, E.S. Pareira, H. Sasaki, S. Noji, Y. Kawakami, K. Yoshida and M. Toda, A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma, Oncotarget 9: ((2018) ), 21569–21579.
[196]	P.Y. Wen, D.A. Reardon, T.S. Armstrong, S. Phuphanich, R.D. Aiken, J.C. Landolfi, W.T. Curry, J.J. Zhu, M. Glantz, D.M. Peereboom, J.M. Markert, R. LaRocca, D.M. O’Rourke, K. Fink, L. Kim, M. Gruber, G.J. Lesser, E. Pan, S. Kesari, A. Muzikansky, C. Pinilla, R.G. Santos and J.S. Yu, A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma, Clin Cancer Res 25: ((2019) ), 5799–5807.
[197]	R. Kikuchi, R. Ueda, K. Saito, S. Shibao, H. Nagashima, R. Tamura, Y. Morimoto, H. Sasaki, S. Noji, Y. Kawakami, K. Yoshida and M. Toda, A pilot study of vaccine therapy with multiple glioma oncoantigen/glioma angiogenesis-associated antigen peptides for patients with recurrent/progressive high-grade glioma, J Clin Med 8: ((2019) ).
[198]	D.B. Keskin, A.J. Anandappa, J. Sun, I. Tirosh, N.D. Mathewson, S. Li, G. Oliveira, A. Giobbie-Hurder, K. Felt, E. Gjini, S.A. Shukla, Z. Hu, L. Li, P.M. Le, R.L. Allesøe, A.R. Richman, M.S. Kowalczyk, S. Abdelrahman, J.E. Geduldig, S. Charbonneau, K. Pelton, J.B. Iorgulescu, L. Elagina, W. Zhang, O. Olive, C. McCluskey, L.R. Olsen, J. Stevens, W.J. Lane, A.M. Salazar, H. Daley, P.Y. Wen, E.A. Chiocca, M. Harden, N.J. Lennon, S. Gabriel, G. Getz, E.S. Lander, A. Regev, J. Ritz, D. Neuberg, S.J. Rodig, K.L. Ligon, M.L. Suvà, K.W. Wucherpfennig, N. Hacohen, E.F. Fritsch, K.J. Livak, P.A. Ott, C.J. Wu and D.A. Reardon, Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial, Nature 565: ((2019) ), 234–239.
[199]	S. Mueller, J.M. Taitt, J.E. Villanueva-Meyer, E.R. Bonner, T. Nejo, R.R. Lulla, S. Goldman, A. Banerjee, S.N. Chi, N.S. Whipple, J.R. Crawford, K. Gauvain, K.J. Nazemi, P.B. Watchmaker, N.D. Almeida, K. Okada, A.M. Salazar, R.D. Gilbert, J. Nazarian, A.M. Molinaro, L.H. Butterfield, M.D. Prados and H. Okada, Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma, J Clin Invest 130: ((2020) ), 6325–6337.
[200]	M. Platten, L. Bunse, A. Wick, T. Bunse, L. Le Cornet, I. Harting, F. Sahm, K. Sanghvi, C.L. Tan, I. Poschke, E. Green, S. Justesen, G.A. Behrens, M.O. Breckwoldt, A. Freitag, L.M. Rother, A. Schmitt, O. Schnell, J. Hense, M. Misch, D. Krex, S. Stevanovic, G. Tabatabai, J.P. Steinbach, M. Bendszus, A. von Deimling, M. Schmitt and W. Wick, A vaccine targeting mutant IDH1 in newly diagnosed glioma, Nature 592: ((2021) ), 463–468.
[201]	Z. Jahanafrooz, B. Baradaran, J. Mosafer, M. Hashemzaei, T. Rezaei, A. Mokhtarzadeh and M.R. Hamblin, Comparison of DNA and mRNA vaccines against cancer, Drug Discov Today 25: ((2020) ), 552–560.
[202]	M.A. McNamara, S.K. Nair and E.K. Holl, RNA-based vaccines in cancer immunotherapy, J Immunol Res 2015: ((2015) ), 794528.
[203]	R. Ueda, E. Kinoshita, R. Ito, T. Kawase, Y. Kawakami and M. Toda, Induction of protective and therapeutic antitumor immunity by a DNA vaccine with a glioma antigen, SOX6, Int J Cancer 122: ((2008) ), 2274–9.
[204]	A. Mintz, D.M. Gibo, A.B. Madhankumar, N.M. Cladel, N.D. Christensen and W. Debinski, Protein- and DNA-based active immunotherapy targeting interleukin-13 receptor alpha2, Cancer Biother Radiopharm 23: ((2008) ), 581–9.
[205]	A. Lopes, C. Bastiancich, M. Bausart, S. Ligot, L. Lambricht, K. Vanvarenberg, B. Ucakar, B. Gallez, V. Préat and G. Vandermeulen, New generation of DNA-based immunotherapy induces a potent immune response and increases the survival in different tumor models, J Immunother Cancer 9: ((2021) ).
[206]	L. Ye, L. Wang, J. Yang, P. Hu, C. Zhang, S. Tong, Z. Liu and D. Tian, Identification of tumor antigens and immune subtypes in lower grade gliomas for mRNA vaccine development, J Transl Med 19: ((2021) ), 352.
[207]	Q. Zhou, X. Yan, H. Zhu, Z. Xin, J. Zhao, W. Shen, W. Yin, Y. Guo, H. Xu, M. Zhao, W. Liu, X. Jiang and C. Ren, Identification of three tumor antigens and immune subtypes for mRNA vaccine development in diffuse glioma, Theranostics 11: ((2021) ), 9775–9790.
[208]	H. Zhong, S. Liu, F. Cao, Y. Zhao, J. Zhou, F. Tang, Z. Peng, Y. Li, S. Xu, C. Wang, G. Yang and Z.Q. Li, Dissecting tumor antigens and immune subtypes of glioma to develop mRNA vaccine, Front Immunol 12: ((2021) ), 709986.
[209]	S. Ma, Y. Ba, H. Ji, F. Wang, J. Du and S. Hu, Recognition of Tumor-Associated Antigens and Immune Subtypes in Glioma for mRNA Vaccine Development, Front Immunol 12: ((2021) ), 738435.
[210]	H. Lin, K. Wang, Y. Xiong, L. Zhou, Y. Yang, S. Chen, P. Xu, Y. Zhou, R. Mao, G. Lv, P. Wang and D. Zhou, Identification of tumor antigens and immune subtypes of glioblastoma for mRNA vaccine development, Front Immunol 13: ((2022) ), 773264.
[211]	Z. Chen, X. Wang, Z. Yan and M. Zhang, Identification of tumor antigens and immune subtypes of glioma for mRNA vaccine development, Cancer Med 11: ((2022) ), 2711–2726.
[212]	E.A. Chiocca, F. Nassiri, J. Wang, P. Peruzzi and G. Zadeh, Viral and other therapies for recurrent glioblastoma: is a 24-month durable response unusual? Neuro Oncol 21: ((2019) ), 14–25.
[213]	G. Marelli, A. Howells, N.R. Lemoine and Y. Wang, Oncolytic viral therapy and the immune system: A double-edged sword against cancer, Front Immunol 9: ((2018) ), 866.
[214]	N.G. Rainov, A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme, Hum Gene Ther 11: ((2000) ), 2389–401.
[215]	T. Mineta, S.D. Rabkin, T. Yazaki, W.D. Hunter and R.L. Martuza, Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas, Nat Med 1: ((1995) ), 938–43.
[216]	J.M. Markert, S.N. Razdan, H.C. Kuo, A. Cantor, A. Knoll, M. Karrasch, L.B. Nabors, M. Markiewicz, B.S. Agee, J.M. Coleman, A.D. Lakeman, C.A. Palmer, J.N. Parker, R.J. Whitley, R.R. Weichselbaum, J.B. Fiveash and G.Y. Gillespie, A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses, Mol Ther 22: ((2014) ), 1048–55.
[217]	G.K. Friedman, J.M. Johnston, A.K. Bag, J.D. Bernstock, R. Li, I. Aban, K. Kachurak, L. Nan, K.D. Kang, S. Totsch, C. Schlappi, A.M. Martin, D. Pastakia, R. McNall-Knapp, S. Farouk Sait, Y. Khakoo, M.A. Karajannis, K. Woodling, J.D. Palmer, D.S. Osorio, J. Leonard, M.S. Abdelbaki, A. Madan-Swain, T.P. Atkinson, R.J. Whitley, J.B. Fiveash, J.M. Markert and G.Y. Gillespie, Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas, N Engl J Med 384: ((2021) ), 1613–1622.
[218]	J.M. Markert, M.D. Medlock, S.D. Rabkin, G.Y. Gillespie, T. Todo, W.D. Hunter, C.A. Palmer, F. Feigenbaum, C. Tornatore, F. Tufaro and R.L. Martuza, Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial, Gene Ther 7: ((2000) ), 867–74.
[219]	E.A. Chiocca, H. Nakashima, K. Kasai, S.A. Fernandez and M. Oglesbee, Preclinical toxicology of rQNestin34.5v.2: An oncolytic herpes virus with transcriptional regulation of the ICP34.5 neurovirulence gene, Mol Ther Methods Clin Dev 17: ((2020) ), 871–893.
[220]	Y. Otani, J.Y. Yoo, C.T. Lewis, S. Chao, J. Swanner, T. Shimizu, J.M. Kang, S.A. Murphy, K. Rivera-Caraballo, B. Hong, J.C. Glorioso, H. Nakashima, S.E. Lawler, Y. Banasavadi-Siddegowda, J.D. Heiss, Y. Yan, G. Pei, M.A. Caligiuri, Z. Zhao, E.A. Chiocca, J. Yu and B. Kaur, NOTCH-Induced MDSC RECRUItment after oHSV virotherapy in CNS cancer models modulates antitumor immunotherapy, Clin Cancer Res 28: ((2022) ), 1460–1473.
[221]	E.A. Adjei-Sowah, S.A. O’Connor, J. Veldhuizen, C. Lo Cascio, C. Plaisier, S. Mehta and M. Nikkhah, Investigating the interactions of glioma stem cells in the perivascular niche at single-cell resolution using a microfluidic tumor microenvironment model, Adv Sci (Weinh) 9: ((2022) ), e2201436.
[222]	D. Hambardzumyan and G. Bergers, Glioblastoma: Defining tumor niches, Trends Cancer 1: ((2015) ), 252–265.
[223]	A. Filatova, T. Acker and B.K. Garvalov, The cancer stem cell niche(s): the crosstalk between glioma stem cells and their microenvironment, Biochim Biophys Acta 1830: ((2013) ), 2496–508.
[224]	P.S. Nakod, Y. Kim and S.S. Rao, Biomimetic models to examine microenvironmental regulation of glioblastoma stem cells, Cancer Lett 429: ((2018) ), 41–53.
[225]	Y. Chonan, S. Taki, O. Sampetrean, H. Saya and R. Sudo, Endothelium-induced three-dimensional invasion of heterogeneous glioma initiating cells in a microfluidic coculture platform, Integr Biol (Camb) 9: ((2017) ), 762–773.
[226]	Y. Xiao, D. Kim, B. Dura, K. Zhang, R. Yan, H. Li, E. Han, J. Ip, P. Zou, J. Liu, A.T. Chen, A.O. Vortmeyer, J. Zhou and R. Fan, Ex vivo dynamics of human glioblastoma cells in a microvasculature-on-a-chip system correlates with tumor heterogeneity and subtypes, Adv Sci (Weinh) 6: ((2019) ), 1801531.
[227]	M.T. Ngo and B.A. Harley, The influence of hyaluronic acid and glioblastoma cell coculture on the formation of endothelial cell networks in gelatin hydrogels, Adv Healthc Mater 6: ((2017) ).
[228]	C. Wang, J. Li, S. Sinha, A. Peterson, G.A. Grant and F. Yang, Mimicking brain tumor-vasculature microanatomical architecture via co-culture of brain tumor and endothelial cells in 3D hydrogels, Biomaterials 202: ((2019) ), 35–44.
[229]	X. Cui, R.T. Morales, W. Qian, H. Wang, J.P. Gagner, I. Dolgalev, D. Placantonakis, D. Zagzag, L. Cimmino, M. Snuderl, R.H.W. Lam and W. Chen, Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis, Biomaterials 161: ((2018) ), 164–178.
[230]	J.M. Ayuso, R. Monge, A. Martínez-González, M. Virumbrales-Muñoz, G.A. Llamazares, J. Berganzo, A. Hernández-Laín, J. Santolaria, M. Doblaré, C. Hubert, J.N. Rich, P. Sánchez-Gómez, V.M. Pérez-García, I. Ochoa and L.J. Fernández, Glioblastoma on a microfluidic chip: Generating pseudopalisades and enhancing aggressiveness through blood vessel obstruction events, Neuro Oncol 19: ((2017) ), 503–513.
[231]	F. Yuan, X. Cai, Z. Cong, Y. Wang, Y. Geng, Y. Aili, C. Du, J. Zhu, J. Yang, C. Tang, A. Zhang, S. Zhao and C. Ma, Roles of the m(6)A modification of RNA in the glioblastoma microenvironment as revealed by single-cell analyses, Front Immunol 13: ((2022) ), 798583.
[232]	R.C. Gimple, K. Yang, M.E. Halbert, S. Agnihotri and J.N. Rich, Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity, Nat Rev Cancer 22: ((2022) ), 497–514.
[233]	W. Zhu, H. Chen, K. Yan, J. Wu, Y. Zhao and Q. Huang, Glioma stem cells and their microenvironment: A narrative review on docking and transformation, Glioma 5: ((2022) ), 12–19.
[234]	R. Stupp, W.P. Mason, M.J. van den Bent, M. Weller, B. Fisher, M.J.B. Taphoorn, K. Belanger, A.A. Brandes, C. Marosi, U. Bogdahn, J. Curschmann, R.C. Janzer, S.K. Ludwin, T. Gorlia, A. Allgeier, D. Lacombe, J.G. Cairncross, E. Eisenhauer and R.O. Mirimanoff, Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma, New England Journal of Medicine 352: ((2005) ), 987–996.
[235]	R. Stupp, M. Brada, M.J. van den Bent, J.C. Tonn and G. Pentheroudakis, High-grade glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up, Ann Oncol 25: (Suppl 3) ((2014) ), iii93–101.
[236]	B. Fazeny-Dörner, C. Wenzel, M. Veitl, M. Piribauer, K. Rössler, K. Dieckmann, K. Ungersböck and C. Marosi, Survival and prognostic factors of patients with unresectable glioblastoma multiforme, Anticancer Drugs 14: ((2003) ), 305–12.
[237]	P. Lesueur, J. Lequesne, J.M. Grellard, A. Dugué, E. Coquan, P.E. Brachet, J. Geffrelot, W. Kao, E. Emery, D.H. Berro, L. Castera, N. Goardon, J. Lacroix, M. Lange, A. Capel, A. Leconte, B. Andre, A. Léger, A. Lelaidier, B. Clarisse and D. Stefan, Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol, BMC Cancer 19: ((2019) ), 198.
[238]	K.R. Yabroff, L. Harlan, C. Zeruto, J. Abrams and B. Mann, Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006, Neuro Oncol 14: ((2012) ), 351–9.
[239]	D.A. Reardon, A.A. Brandes, A. Omuro, P. Mulholland, M. Lim, A. Wick, J. Baehring, M.S. Ahluwalia, P. Roth, O. Bähr, S. Phuphanich, J.M. Sepulveda, P. De Souza, S. Sahebjam, M. Carleton, K. Tatsuoka, C. Taitt, R. Zwirtes, J. Sampson and M. Weller, Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: The CheckMate 143 phase 3 randomized clinical trial, JAMA Oncol 6: ((2020) ), 1003–1010.
[240]	T. Cloughesy, G. Finocchiaro, C. Belda-Iniesta, L. Recht, A.A. Brandes, E. Pineda, T. Mikkelsen, O.L. Chinot, C. Balana, D.R. Macdonald, M. Westphal, K. Hopkins, M. Weller, C. Bais, T. Sandmann, J.M. Bruey, H. Koeppen, B. Liu, W. Verret, S.C. Phan and D.S. Shames, Randomized, double-blind, placebo-controlled, multicenter phase ii study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: efficacy, safety, and hepatocyte growth factor and O(6)-methylguanine-DNA methyltransferase biomarker analyses, J Clin Oncol 35: ((2017) ), 343–351.
[241]	A.F. Haddad, J.S. Young, D. Amara, M.S. Berger, D.R. Raleigh, M.K. Aghi and N.A. Butowski, Mouse models of glioblastoma for the evaluation of novel therapeutic strategies, Neurooncol Adv 3: ((2021) ), vdab100.
[242]	M. Bausart, V. Préat and A. Malfanti, Immunotherapy for glioblastoma: the promise of combination strategies, J Exp Clin Cancer Res 41: ((2022) ), 35.
[243]	H. Luo, R. Hernandez, H. Hong, S.A. Graves, Y. Yang, C.G. England, C.P. Theuer, R.J. Nickles and W. Cai, Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry, Proc Natl Acad Sci USA 112: ((2015) ), 12806–11.
[244]	K.R. Ulapane, B.M. Kopec and T.J. Siahaan, Improving in vivo brain delivery of monoclonal antibody using novel cyclic peptides, Pharmaceutics 11: ((2019) ).
[245]	K.E. Warren, Beyond the Blood: Brain Barrier: The importance of central nervous system (CNS) pharmacokinetics for the treatment of CNS tumors, including diffuse intrinsic pontine glioma, Front Oncol 8: ((2018) ), 239.
[246]	N.D. Sheybani, V.R. Breza, S. Paul, K.S. McCauley, S.S. Berr, G.W. Miller, K.D. Neumann and R.J. Price, ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma, J Control Release 331: ((2021) ), 19–29.
[247]	E.A. Nance, G.F. Woodworth, K.A. Sailor, T.Y. Shih, Q. Xu, G. Swaminathan, D. Xiang, C. Eberhart and J. Hanes, A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue, Sci Transl Med 4: ((2012) ), 149ra119.
[248]	E. Nance, C. Zhang, T.Y. Shih, Q. Xu, B.S. Schuster and J. Hanes, Brain-penetrating nanoparticles improve paclitaxel efficacy in malignant glioma following local administration, ACS Nano 8: ((2014) ), 10655–64.
[249]	L.C.S. Erthal, O.L. Gobbo and E. Ruiz-Hernandez, Biocompatible copolymer formulations to treat glioblastoma multiforme, Acta Biomater 121: ((2021) ), 89–102.
[250]	C. Bastiancich, A. Malfanti, V. Préat and R. Rahman, Rationally designed drug delivery systems for the local treatment of resected glioblastoma, Adv Drug Deliv Rev 177: ((2021) ), 113951.
[251]	C.T. Tsao, F.M. Kievit, A. Ravanpay, A.E. Erickson, M.C. Jensen, R.G. Ellenbogen and M. Zhang, Thermoreversible poly(ethylene glycol)-g-chitosan hydrogel as a therapeutic T lymphocyte depot for localized glioblastoma immunotherapy, Biomacromolecules 15: ((2014) ), 2656–62.
[252]	C. He, H. Ding, J. Chen, Y. Ding, R. Yang, C. Hu, Y. An, D. Liu, P. Liu, Q. Tang and Z. Zhang, Immunogenic cell death induced by chemoradiotherapy of novel pH-sensitive cargo-loaded polymersomes in glioblastoma, Int J Nanomedicine 16: ((2021) ), 7123–7135.
[253]	J. Zhang, C. Chen, A. Li, W. Jing, P. Sun, X. Huang, Y. Liu, S. Zhang, W. Du, R. Zhang, Y. Liu, A. Gong, J. Wu and X. Jiang, Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection, Nat Nanotechnol 16: ((2021) ), 538–548.
[254]	F.A. Bruinsmann, G. Richter Vaz, A. de Cristo Soares Alves, T. Aguirre, A. Raffin Pohlmann, S. Stanisçuaski Guterres and F. Sonvico, Nasal drug delivery of anticancer drugs for the treatment of glioblastoma: Preclinical and clinical trials, Molecules 24: ((2019) ).
[255]	W. Wang, S. Swenson, H.Y. Cho, F.M. Hofman, A.H. Schönthal and T.C. Chen, Efficient brain targeting and therapeutic intracranial activity of bortezomib through intranasal co-delivery with NEO100 in rodent glioblastoma models, J Neurosurg 132: ((2019) ), 959–967.
[256]	H.H. Chung, M.J. Hsieh, Y.S. Hsieh, P.N. Chen, C.P. Ko, N.Y. Yu, C.W. Lin and S.F. Yang, The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells, Pharmaceuticals (Basel) 14: ((2021) ).
[257]	V. Bordoni, L. Sanna, W. Lyu, E. Avitabile, S. Zoroddu, S. Medici, D.J. Kelvin and L. Bagella, Silver nanoparticles derived by artemisia arborescens reveal anticancer and apoptosis-inducing effects, Int J Mol Sci 22: ((2021) ).
[258]	X. Fei, A. Wang, D. Wang, X. Meng, J. Ma, L. Hong, R. Qin, A. Wang, J. Dong, Q. Huang and Z. Wang, Establishment of malignantly transformed dendritic cell line SU3-ihDCTC induced by Glioma stem cells and study on its sensitivity to resveratrol, BMC Immunol 19: ((2018) ), 7.
[259]	B. Majc, M. Novak, N. Kopitar-Jerala, A. Jewett and B. Breznik, Immunotherapy of glioblastoma: Current strategies and challenges in tumor model development, Cells 10: ((2021) ).
[260]	K. Kaur, P. Topchyan, A.K. Kozlowska, N. Ohanian, J. Chiang, P.O. Maung, S.H. Park, M.W. Ko, C. Fang, I. Nishimura and A. Jewett, Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs, Oncoimmunology 7: ((2018) ), e1426518.
[261]	T.A. Cheema, H. Wakimoto, P.E. Fecci, J. Ning, T. Kuroda, D.S. Jeyaretna, R.L. Martuza and S.D. Rabkin, Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model, Proc Natl Acad Sci USA 110: ((2013) ), 12006–11.
[262]	F. Merz, F. Gaunitz, F. Dehghani, C. Renner, J. Meixensberger, A. Gutenberg, A. Giese, K. Schopow, C. Hellwig, M. Schäfer, M. Bauer, H. Stöcker, G. Taucher-Scholz, M. Durante and I. Bechmann, Organotypic slice cultures of human glioblastoma reveal different susceptibilities to treatments, Neuro Oncol 15: ((2013) ), 670–81.
[263]	J.J. Parker, M. Lizarraga, A. Waziri and K.M. Foshay, A human glioblastoma organotypic slice culture model for study of tumor cell migration and patient-specific effects of anti-invasive drugs, J Vis Exp ((2017) ).
[264]	X. Jiang, Y.D. Seo, K.M. Sullivan and V.G. Pillarisetty, Establishment of slice cultures as a tool to study the cancer immune microenvironment, Methods Mol Biol 1884: ((2019) ), 283–295.
[265]	L. Ciraku, R.A. Moeller, E.M. Esquea, W.A. Gocal, E.J. Hartsough, N.L. Simone, J.G. Jackson and M.J. Reginato, An ex vivo brain slice model to study and target breast cancer brain metastatic tumor growth, J Vis Exp ((2021) ).
[266]	D. Truong, R. Fiorelli, E.S. Barrientos, E.L. Melendez, N. Sanai, S. Mehta and M. Nikkhah, A three-dimensional (3D) organotypic microfluidic model for glioma stem cells – Vascular interactions, Biomaterials 198: ((2019) ), 63–77.
[267]	M.A. Koppens, G. Bounova, P. Cornelissen-Steijger, N. de Vries, O.J. Sansom, L.F. Wessels and M. van Lohuizen, Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition, Oncotarget 7: ((2016) ), 69816–69828.
[268]	J. Yu, B. Qin, A.M. Moyer, S. Nowsheen, T. Liu, S. Qin, Y. Zhuang, D. Liu, S.W. Lu, K.R. Kalari, D.W. Visscher, J.A. Copland, S.A. McLaughlin, A. Moreno-Aspitia, D.W. Northfelt, R.J. Gray, Z. Lou, V.J. Suman, R. Weinshilboum, J.C. Boughey, M.P. Goetz and L. Wang, DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine, J Clin Invest 128: ((2018) ), 2376–2388.
[269]	F. Jacob, R.D. Salinas, D.Y. Zhang, P.T.T. Nguyen, J.G. Schnoll, S.Z.H. Wong, R. Thokala, S. Sheikh, D. Saxena, S. Prokop, D.A. Liu, X. Qian, D. Petrov, T. Lucas, H.I. Chen, J.F. Dorsey, K.M. Christian, Z.A. Binder, M. Nasrallah, S. Brem, D.M. O’Rourke, G.L. Ming and H. Song, A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity, Cell 180: ((2020) ), 188–204e22..
[270]	M.J. Rybin, M.E. Ivan, N.G. Ayad and Z. Zeier, Organoid models of glioblastoma and their role in drug discovery, Front Cell Neurosci 15: ((2021) ), 605255.
[271]	C. Zhang, M. Jin, J. Zhao, J. Chen and W. Jin, Organoid models of glioblastoma: advances, applications and challenges, Am J Cancer Res 10: ((2020) ), 2242–2257.
[272]	R. Azzarelli, Organoid models of glioblastoma to study brain tumor stem cells, Front Cell Dev Biol 8: ((2020) ), 220.
[273]	A. Linkous, D. Balamatsias, M. Snuderl, L. Edwards, K. Miyaguchi, T. Milner, B. Reich, L. Cohen-Gould, A. Storaska, Y. Nakayama, E. Schenkein, R. Singhania, S. Cirigliano, T. Magdeldin, Y. Lin, G. Nanjangud, K. Chadalavada, D. Pisapia, C. Liston and H.A. Fine, Modeling patient-derived glioblastoma with cerebral organoids, Cell Rep 26: ((2019) ), 3203–3211e5..
[274]	J. Ogawa, G.M. Pao, M.N. Shokhirev and I.M. Verma, Glioblastoma model using human cerebral organoids, Cell Rep 23: ((2018) ), 1220–1229.
[275]	F. Andreatta, G. Beccaceci, N. Fortuna, M. Celotti, D. De Felice, M. Lorenzoni, V. Foletto, S. Genovesi, J. Rubert and A. Alaimo, The organoid era permits the development of new applications to study glioblastoma, Cancers (Basel) 12: ((2020) ).
[276]	T.G. Krieger, S.M. Tirier, J. Park, K. Jechow, T. Eisemann, H. Peterziel, P. Angel, R. Eils and C. Conrad, Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics, Neuro Oncol 22: ((2020) ), 1138–1149.
[277]	S. Bian, M. Repic, Z. Guo, A. Kavirayani, T. Burkard, J.A. Bagley, C. Krauditsch and J.A. Knoblich, Genetically engineered cerebral organoids model brain tumor formation, Nat Methods 15: ((2018) ), 631–639.
[278]	G. Goranci-Buzhala, A. Mariappan, E. Gabriel, A. Ramani, L. Ricci-Vitiani, M. Buccarelli, Q.G. D’Alessandris, R. Pallini and J. Gopalakrishnan, Rapid and efficient invasion assay of glioblastoma in human brain organoids, Cell Rep 31: ((2020) ), 107738.
[279]	J.G. Camp, F. Badsha, M. Florio, S. Kanton, T. Gerber, M. Wilsch-Bräuninger, E. Lewitus, A. Sykes, W. Hevers, M. Lancaster, J.A. Knoblich, R. Lachmann, S. Pääbo, W.B. Huttner and B. Treutlein, Human cerebral organoids recapitulate gene expression programs of fetal neocortex development, Proc Natl Acad Sci USA 112: ((2015) ), 15672-7.
[280]	A.A. Pollen, A. Bhaduri, M.G. Andrews, T.J. Nowakowski, O.S. Meyerson, M.A. Mostajo-Radji, E. Di Lullo, B. Alvarado, M. Bedolli, M.L. Dougherty, I.T. Fiddes, Z.N. Kronenberg, J. Shuga, A.A. Leyrat, J.A. West, M. Bershteyn, C.B. Lowe, B.J. Pavlovic, S.R. Salama, D. Haussler, E.E. Eichler and A.R. Kriegstein, Establishing cerebral organoids as models of human-specific brain evolution, Cell 176: ((2019) ), 743–756e17..
[281]	S. Velasco, A.J. Kedaigle, S.K. Simmons, A. Nash, M. Rocha, G. Quadrato, B. Paulsen, L. Nguyen, X. Adiconis, A. Regev, J.Z. Levin and P. Arlotta, Individual brain organoids reproducibly form cell diversity of the human cerebral cortex, Nature 570: ((2019) ), 523–527.
[282]	C.E. Brown, S. Bucktrout, L.H. Butterfield, O. Futer, E. Galanis, A. Hormigo, M. Lim, H. Okada, R. Prins, S.S. Marr and K. Tanner, The future of cancer immunotherapy for brain tumors: a collaborative workshop, J Transl Med 20: ((2022) ), 236.
[283]	A.L. Johnson, J. Laterra and H. Lopez-Bertoni, Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities, Front Oncol 12: ((2022) ), 995498.
[284]	X. Zhu, Y. Fang, Y. Chen, Y. Chen, W. Hong, W. Wei and J. Tu, Interaction of tumor-associated microglia/macrophages and cancer stem cells in glioma, Life Sci 320: ((2023) ), 121558.
[285]	A. Wang, X. Dai, B. Cui, X. Fei, Y. Chen, J. Zhang, Q. Zhang, Y. Zhao, Z. Wang, H. Chen, Q. Lan, J. Dong and Q. Huang, Experimental research of host macrophage canceration induced by glioma stem progenitor cells, Mol Med Rep 11: ((2015) ), 2435–42.