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Review

Current Understanding Regarding the Glioma Microenvironment and Impact of the Immune System

by
Enes Demir
1,
Deondra Montgomery
2,
Ammar Saloum
2,
Nasser Yaghi
3 and
Michael Karsy
3,*
1
School of Medicine, Eskisehir Osmangazi University, Eskişehir 26040, Türkiye
2
College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
3
Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Neuroglia 2025, 6(1), 13; https://doi.org/10.3390/neuroglia6010013
Submission received: 30 October 2024 / Revised: 1 February 2025 / Accepted: 20 February 2025 / Published: 7 March 2025
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Abstract

:
High-grade gliomas are aggressive, primary, central nervous system tumors with low survival rates due to recurrence and resistance to current therapy models. Recent studies have highlighted the importance between the interaction of glioma cancer cells and cells of the tumor microenvironment (TME). Cancer stem cells and immune cells play a critical role in the TME of gliomas. TMEs in glioma include the perivascular TME, hypoxic TME, and invasive TME, each of which have evolved as our understanding of the involved cellular players has improved. This review discusses the multidimensional aspects of the current targeted therapies and interactions between glioma cells and the TME with specific focus on targeted immunotherapies. Understanding the complexities of the TME and elucidating the various tumor-cell interactions will be critical for facilitating the development of novel precision strategies, ultimately enabling better patient outcomes.

1. Introduction

Gliomas are a diverse group of primary central nervous system tumors that affect both adults and children and represent the most common primary aggressive brain tumors [1,2]. High-grade gliomas (HGG), namely isocitrate dehydrogenase 1 (IDH1) wild-type glioblastoma (GBM), have an incidence of 10 to 20,000 cases annually and a median survival of 14 to 16 months with standard care treatment [1,2]. New effective treatment options for this disease have remained limited. Recent studies have aimed to better understand the tumor microenvironment (TME) and use immunological approaches towards targeted therapy [3,4,5,6]. The glioma TME represents the interaction of tumor cells with neuronal and glial cells, stromal support cells, microvasculature, and local immune environment, each of which interact in complex ways. Genetic alterations in tumor cells can lead to angiogenesis, increased resistance to cell death, and limitless proliferation with impacts on patient prognosis and treatment resistance. Many of the known genetic alterations in HGG also play key roles in the TME (Table 1). This review aims to discuss the role of inflammatory mediators and the immune system in the glioma microenvironment, and possible therapeutic target strategies.

2. TME of HGG and Involved Cells/Signaling Pathways

2.1. Glioma Stem Cells

A critical component of the TME involves the cellular interaction between glioma stem cells (GSCs), neuronal cells, and the immune system [7]. GSCs have a high capability of proliferation, self-renewal, and specialization with a potential for tumor initiation. Current theories on cancer resistance suggest the presence of a GSC population that circumvents traditional treatment approaches. GSCs can also lead to immune evasion and therapy resistance. GSCs contribute to inter- and intra-tumor heterogeneity. Current models of glioma development suggest that lack of targeting the GSC population and associated microenvironment may play a critical role in treatment resistance.
GSCs reside in close relationship with the vessels in a perivascular niche indicating an association with increased angiogenesis and invasiveness [7] as well as distinctly in the hypoxic niche, regulated by HIF-1 signaling pathways [8]. CD133, a cell-surface protein encoded by the PROM1 gene, is used to identify GSCs [9]. However, it was found that CD133-negative cells also have the potential for tumor initiation, suggesting that CD133 is not an exclusive biomarker for GSCs. Additional cell surface markers such as A2B5, CD15, CD 44, CD90, integrin alpha-6, L1CAM, and additional intracellular markers such as BMI1, MYC, NESTIN, OLIG2, and SOX2 have been identified in GSCs [10].

2.2. Identification of the TME

Several TME niches may be present in HGG with distinct cell populations and pathways (Figure 1, Figure 2 and Figure 3) [3,7]. Classically, the HGG microenvironment was first described by neuropathologist Hans Joachim Scherer, who observed the ability of tumor cells to invade along white matter tracts and vasculature away from the tumor borders [11]. The term “perineuronal satellitosis” defined the presence of glioma cells around normal neurons. More recent discoveries with serial sampling outside of active HGG tumor zones have indicated the potential for tumor invasion into normal brain [12,13], and single-cell sequencing techniques have highlighted the genotypic and phenotypic heterogeneity of HGG tumor populations [14,15,16]. The TME has been redefined as the perivascular, hypoxic, and invasive niches, which may offer a more accurate method of understanding the unique tumor biology. The addition of the peri-arteriolar vascular niche, extracellular matrix niche, and immune niches have also been recently defined [17]. These various TME often overlap significantly and share common signaling pathways despite their distinct impact on tumor biology.

2.3. Perivascular TME

The perivascular TME defines a hypervascular environment with vascular proliferation and increased presence of abnormal and immature microvessels, along with upregulated vascular endothelial growth factor (VEGF), TNF-alpha, IL-6, and IL-8 [3,7]. Tumor-associated macrophages (TAMs) have also been highly associated with the perivascular TME. Isolated GSCs from patient tumors showed an increased ability to promote vasculogenesis and upregulate VEGF activity when implanted in immune-compromised orthotopic models [18]. Moreover, these upregulated vascular effects were limited using anti-VEGF antibody therapy, only in GSC-derived tumor models. Others have shown the ability of matrix metalloproteinase 1, epidermal growth factor (EGFR), and platelet-derived growth factor to also impact the perivascular TME [19]. Patient treatment with VEGF inhibitors, such as bevacizumab, has ultimately not been shown clinically to improve overall survival despite improvements in progression-free survival and reduced contrast enhancement, highlighting the impact on the perivascular TME without durable survival benefit [20]. In addition to the perivascular TME, the periarteriolar TME has been suggested as a unique environment, closer in structure to the hematopoietic cells of the bone marrow, which has unique molecular signaling pathways and involved downstream regulating enzymes compared with the perivascular TME [21].

2.4. Hypoxic TME

The hypoxic TME embodies a classic area of tumor biology under investigation in HGG [3,7]. Given the rapid growth of tumor cells and limited ability to both recruit normal blood vessels (angiogenesis) and generate new blood vessels (neoangiogenesis), the hypoxic environment defines an area with high levels of cell necrosis, elevated HIF1-alpha signaling, and low oxygen tension levels. The hypoxic environment triggers anaerobic glycolysis, termed the Warburg effect, and promotes angiogenesis, cellular senescence, cellular reprogramming, and immune cell infiltration in HGG [22]. The anaerobic glycolysis produces more lactic acid, which lowers the pH level and drives the propagation of an acidic environment. This hostile microenvironment cycle, created by its acidic and hypoxic properties, can induce immune evasion and resistance to potential therapies (e.g., alkylating chemotherapies, radiation therapy).
Several pathways are involved in the regulation of the hypoxic TME. Upregulated O-6-methylguanine-DNA methyltransferase (MGMT), a key DNA repair enzyme involved in resistance to alkylating chemotherapies, can be seen in hypoxic environments of HGG in an oxygen gradient-dependent manner [23]. More recent studies have indicated that hypoxic environments can induce epithelial-mesenchymal transitions in HGG, which correlate with worse patient prognosis [15,24]. The regulation of hypoxic signaling in HGG is complex, involving multiple regulatory pathways and signaling events [25,26,27,28]. Key regulators of the hypoxic TME include the following: (1) HIF-1alpha and HIF-2, which promote hypoxic signaling and reduce immune infiltration [8]; (2) VEGF and IL-8, which can promote CD133 cell proliferation [29]; (3) the WNT pathway, which can upregulate MGMT activity [30]; and (4) EGFR/mTOR, which mediate tumor proliferation [31]. Newer studies have more strongly supported the role of the hypoxic TME in regulating GSCs [3,7].

2.5. Invasive TME

The invasive HGG microenvironment defines the infiltrative edge of the tumor’s involvement with the normal brain. This is mainly regulated by CXCL12/CXCR4 upregulation and GSC stimulation by ligands, including notch, angiopeptin, or endothelial chemokines [32,33]. Tumor cells may crosstalk with endothelial cells to promote infiltration, proliferation, and vasculogenesis. HGG remodeling of the extracellular membrane involves the secretion of proteases, namely matrix metalloproteinase (MMP) 1, 2, 9, and 14, as well as disintegrin and metalloproteinases [34]. Tumors can also recruit microglia, astrocytes, and endothelial cells to promote protease secretion. The extracellular matrix TME has also been suggested as a unique environment, comprised of GSCs, upregulated hypoxia signaling molecules, and specifically secreted protein by GSC, such as laminin [3,7,35].

3. Interaction Between the Glioma Tumor Cells and the Immune System

3.1. Role of Blood-Brain-Barrier; Changes in HGG

The brain microenvironment had been classically viewed as being “immune privileged”, with the blood-brain-barrier (BBB) playing an important role in this classification. The permeability of the BBB is minimal due to the tight junctions between the endothelial cells in the vasculature, the pericytes, astrocyte foot processes, and active transport systems [36,37]. This impermeability and controlled access to the brain creates an environment in which brain tumors can grow without the distinct immune surveillance observed in other organs. Accumulating evidence shows the function of a “glymphatic system” in the brain in connecting to the deep cervical lymph nodes and providing an avenue for immune cell entry into the brain [38,39,40,41]. More recent studies demonstrate the interplay of the peripheral immune system with recognized T cell entry within the brain, as well as interaction of the endogenous microglial system of the brain and TME [42]. Another avenue for immune cell entry occurs when the integrity of the BBB is compromised, such as in diseased states. As HGG grows, it can physically distort the BBB, leading to inflammation and endothelial leakiness due to the compromising of tight junctions in the BBB [37].

3.2. Tregs and Their Involvement in HGG

CD4+ regulatory T cells (Tregs) are suppressor cells of the adaptive immune system that constitutively express the IL-2 receptor α-chain (CD25) and the transcription factor FoxP3 [43,44]. Their role is to maintain immunological tolerance to self-antigens but also limit antitumor immune responses. They are found to accumulate in various tumors, including gliomas. The glioma microenvironment utilizes soluble mediators to recruit Tregs, which can then seek out and inhibit CD8+ cytotoxic T cells [45]. An analysis of a transgenic mouse model of spontaneous glioma revealed that Tregs began infiltrating the brain before tumor-related symptoms developed [46]. This can be attributed to the activation signals that are delivered to lymph nodes, which polarize the differentiated T cells toward the site of insult, such as a growing tumor site. Glioma cells can promote the accumulation of Tregs [47,48], which restrain the antitumor immune response through a variety of mechanisms, including inhibiting T cells via CTLA-4 [49], activation of perforin/granzyme cell death pathways [50], suppression of IL-2 and interferon-γ secretion [51], or secretion of TGF-β [52].
The immune-suppressing effect that Tregs exhibit may be seen in vaccine therapies. Vaccines targeting glioma-associated self-antigens are generally viewed as safe, but the induction of an efficacious antitumor immunity may be hampered by the fact that many of these self-antigens are expressed in the thymus, resulting in central T cell tolerance and the development of antigen-specific suppressive T-regulatory cells [53,54]. The antitumor effects of Treg cells were also shown in several models of Treg depletion/inactivation, showing enhanced vaccine-induced immunity or spontaneous immunity [55,56,57,58]. Blockage of Treg activity via targeting of CTLA-4 [59], inhibiting STAT3 [60], targeting CD25 [61], or alkylating chemotherapy [62] may be required strategies to overcome immune suppression in conjunction with traditional therapies.

3.3. NK Cells and Their Involvement in HGG

Natural killer (NK) cytotoxic lymphocytes are a critical subpopulation in the immunosuppression of the glioma microenvironment. NK cells are primarily CD56+CD3− cells and the main effector of the innate immune system targeting malignancy [63]. NK cell activation and inhibition are complex and altered in gliomas [64]. NK inhibition can be mediated by a number of mechanisms, such as TGF-beta secretion, LDH5 release, expression of galectin 1, or regulation by other immune cells, such as the myeloid Gr-1+CD11b+ population [63,64,65]. Immune suppression of NK cells by Treg cells is a key mechanism of glioma-mediated immune suppression [66].

3.4. Neutrophils

Neutrophils play an important role in the glioma microenvironment. The widespread presence of neutrophil infiltration in HGG areas has been known to impact prognosis [43,44]. While low in number in the brain, the ratio of neutrophils to lymphocytes in gliomas has continued to show a diagnostic and prognostic value, with higher ratios correlating with a lower overall survival and HGG [67]. However, more recent studies have helped identify the nuances in neutrophil subtypes within tumors, namely N1/2, tumor-associated neutrophils, and polymorphonuclear myeloid-derived suppressor cells.
In 2009, Fridlender et al. [68] first classified the neutrophils found in the TME as N1 or N2, with N1 having an antitumor role and N2 having a pro-tumor role. The N1 neutrophils show enhanced antigen presentation, greater phagocytic activity, stronger cytotoxicity, and increased production of pro-inflammatory cytokines. The N2 neutrophils were found to exhibit the opposite, including higher expression of CXCR4, MMP 9, VEGF, and ARG1. Reliable markers for N1 and N2-state neutrophils remain challenging to distinguish. Interferon-1β or blockade of TGF-β resulted in N1 neutrophil aggregation [43,44].

3.5. Tumor-Associated Macrophages and Their Involvement in HGG

Most immune cells found in the glioma microenvironment are macrophages [69]. Tumor-associated-macrophages (TAMs) consist of two different populations that infiltrate and reside within the TME to either promote tumor progression, M2, or tumor suppression, M1 [70,71]. There are several proposed mRNA markers to differentiate between M1 and M2 macrophages, including Arg1, Mrc1, Chi3l3, Socs2, CD163, Fizz-1, and Ccl2 for M2 and Nos2, IL12b, and Ciita for M1 [72]. Between these two TAM phenotypes, it is the M2 macrophages that have been observed to compose most of the TAMs in the glioma microenvironment, pointing to their importance in maintaining a tumor state [73].
In addition to being more prominent in the glioma TME, the M2 phenotype includes an upregulation of immune checkpoints and other inhibitory molecules that are important in promoting tumorigenesis, including increased expression of programmed death-ligand 1 (PD-L1) [74,75]. Expression of PD-L1 is predominantly seen on the TAMs, as opposed to the glioma tumor cells, further pointing to the key role TAMs play in tumor promotion. Glioma-mediated immunosuppression is dependent on the local production of cytokines and chemokines and the recruitment of antitumor immune cells [72]. Specifically, glioma-associated microglia/macrophages (GAMs) promote this tumorigenesis environment. GAMs directly mediate the energy, exhaustion, and apoptosis of lymphocytes by expressing PD-L1 and FasL, as well as secreting immunosuppressive cytokines such as TGF-β, IL-10, IL-6, CSF-1, VEGF, PGE2, NO, Arg I, IDO, and Gal-1 [76,77,78].

4. Interactions Between Glioma Tumor Cells and the Normal Brain Environment

Interactions between glioma tumor cells and normal brain cells play a crucial role in determining glioma response to therapy, largely with the TME modulating tumor growth, invasion, and resistance [79]. Gliomas, particularly high-grade forms like GBM, are not isolated malignancies, and they establish a complex and dynamic relationship with surrounding neurons, glial cells, and vasculature, exploiting normal brain processes for their progression.

4.1. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptors (AMPARs)

The establishment of synaptic-like communication between glioma cells and neurons, resembling the synaptic integration seen in neurodevelopment, harnesses neuronal activity for their proliferation and invasion. These synapses, mediated by glutamatergic signaling through the calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), allow glioma cells to respond to neuronal glutamate release, leading to intracellular calcium elevation and tumor cell migration [80]. Blocking these synaptic interactions has shown the potential to reduce glioma growth and invasiveness, highlighting their therapeutic significance.

4.2. Extracellular Vesicles (EVs)

Another critical aspect of glioma-normal brain cell interactions is the role of extracellular vesicles (EVs) loaded with signaling molecules, oncogenic proteins, RNA, and microRNA. Gliomas utilize EVs to facilitate communication with non-tumor brain cells, altering the function of neurons, astrocytes, and endothelial cells, thereby remodeling the TME in favor of glioma progression [81]. EV-mediated communication not only creates a supportive TME but also facilitates resistance to therapy by transferring resistance-conferring molecules between glioma cells and other cell types. The ability of EVs to cross the blood-brain barrier further underscores their significance as both biomarkers for glioma progression and targets for therapeutic intervention. Blocking EV release has been shown to reduce glioma proliferation and invasion, suggesting that targeting EV-mediated communication could be a viable therapeutic approach [81].

4.3. Scherer Secondary Structures

Glioma cells exhibit a unique ability to infiltrate neural tissue by exploiting pre-existing neuronal and glial structures [79]. This invasive behavior is epitomized by the formation of Scherer secondary structures, including perineuronal satellitosis and perivascular satellitosis. These structures enable glioma cells to surround and infiltrate along neurons, blood vessels, and white matter tracts, facilitating their spread within the brain.
Perineuronal satellitosis, specifically, underscores the intimate interaction between glioma cells and neurons, as glioma cells form clusters around neuronal cell bodies, exploiting them for metabolic and structural support. Recent findings suggest that these perineuronal glioma cells are particularly resistant to therapy, as they reside in a microenvironment that is both protective and conducive to invasion [12,13].

4.4. Tumor Microtubes (TMs)

Neuronal activity induces the formation of tumor microtubes (TMs), which can enhance tumor cell invasion and therapeutic resistance [82]. TM for long, thin protrusions extend from glioma cells and serve as conduits for cell–cell communication, interconnecting tumor cells into a highly resistant network. GBM has been shown to integrate into neuronal networks through TMs, forming resistant tumor networks that mimic neural structures. These interactions, coupled with glutamatergic synaptic inputs, result in an increase in intracellular calcium levels in glioma cells, further promoting invasive and proliferative behaviors. These interactions emphasize the glioma’s ability to hijack normal brain mechanisms, including those of neuronal progenitors and oligodendrocyte precursor cells, which are thought to serve as cells of origin in gliomas [82].

4.5. Neuron-Glioma Cross-Talk and Neuroligin-3 (NLGN3)

Neuroligin-3 (NLGN3), a synaptic adhesion protein secreted by neurons in a neuronal activity-dependent manner, emerges as a critical factor in glioma progression. NLGN3 promotes glioma growth by activating multiple oncogenic signaling pathways, including FAK, PI3K-mTOR, and SRC [83]. Knockout studies in mice have shown that glioma growth is significantly reduced in the absence of NLGN3, highlighting its importance as a therapeutic target. The sheddase ADAM10, responsible for NLGN3 cleavage, has been identified as another potential target [84].

4.6. Astrocytes

In addition to neurons, astrocytes play a pivotal role in shaping the glioma TME. Astrocytes are the most abundant glial cells in the brain and are known to support neuronal function and repair under normal conditions. However, in the presence of glioma cells, astrocytes adopt a tumor-supportive phenotype. Reactive astrocytes secrete cytokines, growth factors, and extracellular matrix components that promote glioma proliferation, invasion, and immune evasion [80]. Regulation of the TME metabolic pathway is also dependent on these cells. Astrocytic gap junctions with glioma cells, facilitating exchange of small molecules that contribute to tumor progression and treatment resistance, may serve as one potential treatment target site.

4.7. Potential Target: Interactions Between Glioma Tumor Cells and Normal Brain Cells

Gliomas are characterized by their invasive nature and the inability of conventional therapies, such as surgery, radiation, and chemotherapy, to fully eradicate the tumor due to its integration into normal brain circuits. This necessitates an in-depth exploration of glioma-normal brain cell interactions to develop targeted therapeutic strategies. Therapeutically, targeting the interactions between glioma cells and the normal brain microenvironment offers significant potential for an effective treatment. Disrupting neuron-glioma synapses, blocking glutamatergic signaling, inhibiting EV release or TM remodeling have been shown to reduce tumor growth and invasion in preclinical models [79]. These strategies can be combined with targeting of the TME.

5. Targeting the Immune System to Treat HGG

Various strategies have been evaluated to treat glioma including augmentation of the innate and adaptive immune systems, as well as more novel treatments, including adoptive immunotherapy, use of checkpoint inhibitors, and immune-modulating vaccines (Figure 4, Table 2).

5.1. Innate Immune Treatment

Two specific cytokines that play a complex role in glioma are IL-10 and TGF-β [85]. IL-10 inhibits the activation and effector functions of dendritic cells, macrophages, and T cells while also upregulating PD-L1 in GAMs [85]. In contrast to this, research has shown that T cells’ inhibition of glioma growth relies on high levels of IL-10 and that IL-10 can stimulate macrophages to produce antiangiogenic cytokines and promote antitumor NK-cell responses [86].
TGF-β has been isolated from patients with glioma and is considered an important immunosuppressive factor. TGF-β expression levels correlate with higher tumor grades and worse prognosis, as well as blockade of T-cell activation and proliferation, in addition to the induction of Tregs [87,88,89]. It has been observed that in the early stages of tumor growth, TGF-β acts as a tumor suppressor; however, at later stages, glioma cells stop responding to these TGF-β-mediated inhibitory signals, and instead, TGF-β enhances tumor progression [90,91].
Another key area of exploration has been in IL-2 treatment. Early trials with the use of IL-2 targeted therapy for the treatment of glioma and several other solid tumors has had limited overall success [92]. Improved understanding of the function of IL-2 to augment the immune system, improve penetration of NK cells and cytotoxic T cells, and integrate with other checkpoint inhibitors has led to a resurgence of interest in the use of interleukin treatment for immunomodulation.

5.2. Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) enhance antitumor immunity by blocking inhibitory molecules on T cells, leading to increased immune responses against cancer. The two primary targets for ICIs approved by the U.S. Food and Drug Administration (FDA) are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2 [93]. CTLA-4 competes with CD28 for binding to B7 molecules on antigen-presenting cells (APCs), and its higher affinity inhibits the co-stimulation needed for full T-cell activation, resulting in immune suppression. Anti-CTLA-4 (i.e., ipilimumab) therapy blocks this inhibition, allowing CD28 to bind to B7 and maintain T-cell activity. Similarly, PD-1 is expressed on activated T cells, while PD-L1 and PD-L2 are present on APCs and some tumor cells; the interaction between PD-1 and its ligands dampens T-cell activity. Blocking this interaction with PD-1 inhibitors such as nivolumab, pembrolizumab, and cemiplimab, or PD-L1 inhibitors such as atezolizumab, durvalumab, and avelumab, restores T-cell function.
While ICIs have been effective in some solid tumors, such as pembrolizumab and nivolumab, significantly improving survival in metastatic melanoma and non-small cell lung cancer, as well as in vivo treatment of glioma, they have been limited clinically in human treatments [85,93,94,95,96]. Several more recent trials have aimed at combining traditional CTLA-4 and PD-1 ICIs with other immune checkpoints such as TIM-3, LAG-3 (NCT02658981), IDO1 (NCT04047706), as well as TIM-3, CD137, and adenosine A2a receptors, which are being investigated as potential therapeutic targets for gliomas [97,98,99].

5.3. Chimeric Antigen Receptor (CAR) T Cells

Chimeric antigen receptor (CAR) T-cell therapy offers a novel immunotherapeutic approach to treating GBM by reprogramming T cells to target tumor-specific antigens [43,93]. This strategy combines the antigen-binding properties of antibodies with T-cell effector functions by fusing the variable region of an antibody with transmembrane and intracellular signaling domains, such as the CD3ζ chain.
Preclinical studies demonstrate that CAR T cells targeting interleukin-13 receptor alpha 2 (IL13Rα2), highly expressed in GBM and absent from healthy tissue, significantly reduce tumor activity [100]. IL13Rα2 is also found on GSCs, and CAR T-cell treatment in animal models has been shown to suppress glioma-initiating activity, indicating the therapy’s potential to target resistant cell populations [100].
In addition to IL13Rα2, other antigens have been targeted in CAR T-cell therapy for GBM, including human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII) [101,102,103]. EGFRvIII is particularly promising, as it is selectively expressed on certain GBM cells but absent from normal brain tissue, minimizing off-target effects.
A Phase I clinical trial (NCT02209376) explored the feasibility of using EGFRvIII-specific CAR T cells in patients with recurrent GBM [104]. Results showed that the modified T cells infiltrated brain tumors and exhibited antitumor activity. However, compensatory immunosuppressive pathways were activated, including increased expression of IDO1, PD-L1, and the recruitment of Tregs, which highlights the need for strategies to overcome immune evasion.
Another Phase I trial (NCT01109095) examined the safety of CAR T cells targeting HER2 in glioma patients using CMV-specific cytotoxic T lymphocytes [105]. The study reported no dose-limiting toxicities, and among the 17 participants, 8 showed clinical benefits—1 with a partial response and 7 with stable disease. These results underscore the potential of CAR T-cell therapy for GBM but also point to the need for further research to optimize its efficacy and overcome the challenges posed by tumor heterogeneity.

5.4. Tumor Vaccines

Dendritic cell vaccine therapy has been evaluated in glioma, aiming to improve cytotoxic T-cell targeting of tumors and activating T-helper cells, termed active immunotherapy [93]. First evaluated in 2000, dendritic cell vaccines show promise in animal models of glioma [106]. The use of pulsed lysate from an EGFRvIII glioma cell line produced intracranial tumor response and improved animal survival. Phase 3 trials of dendritic cell vaccine therapy have shown some tumor response with improved survival [107]. Current strategies to improve antigenic targets have evaluated IDH1, whole-tumor cell lysate, and mRNA-developed targets [107,108,109].

5.5. Oncolytic Viral Therapies

Oncolytic viruses (OVs) are viruses that selectively infect and lyse cancer cells, resulting in cell death, the release of active virus particles, and the presentation of tumor antigens [93]. Additionally, OVs activate both the innate and adaptive immune systems, drawing immune cells to the TME. Various viruses, including herpes simplex virus (HSV), parvovirus, adenovirus, measles virus, and replicating retroviral vectors, have been tested in preclinical studies and early phase clinical trials [93]. HSV-1 variants with mutations in ICP34.5 and ribonucleotide reductase (RNR) have shown safety in Phase I trials and are undergoing Phase II testing [110,111]. Meanwhile, other HSV-1 variants, such as M032 and rQNestin34.5, remain in preclinical development [112].
Several OVs have produced promising results in Phase I/II trials for GBM. These include measles virus MV-CEA, adenovirus DNX-2401 (Ad5-delta24-RGD), polio-rhinovirus chimera (PVSRIPO), parvovirus H-1 (ParvOryx), and retroviral vector Toca 511 (vocimagene amiretrorepvec) with Toca FC (flucytosine) [93]. However, a Phase III randomized controlled trial of Toca 511 (NCT02414165) failed to demonstrate a survival or efficacy benefit over standard care [113]. PVSRIPO, an attenuated polio-rhinovirus chimera, is currently under investigation in a Phase I trial (NCT01491893) after showing efficacy in preclinical models [114]. PVSRIPO was delivered intratumorally to patients with recurrent supratentorial grade IV malignant gliomas. There were some safety concerns because 19% of patients produced grade 3 or higher adverse events, but 20% of them survived for 57 to 70 months following treatment.
Despite some encouraging outcomes, a meta-analysis found no statistically significant difference in survival between patients treated with OVs and those receiving standard care for recurrent GBM [115]. Larger randomized Phase II/III trials are necessary to evaluate the efficacy of oncolytic viral therapy.

6. Conclusions

Treatment of HGG, specifically GBM, still poses a significant challenge due to immune evasion, recurrences, and resistance to the therapy. The dynamic interaction between the TME and glioma cells plays a critical role in prognosis and treatment success.
We highlighted the components of the TME and discussed current treatment strategies. By focusing on the interaction between the glioma cells and the immune system, as well as the TME niches, we elucidated the role of the TME in tumor propagation and treatment resistance.
The highly immunosuppressive conditions created by this complex and multifaceted environment make designing successful therapy challenging. Treatment options targeting specific components, such as immune checkpoint inhibitors or regulatory T cells, have limited clinical success due to immune invasion. Novel therapeutic strategies, including oncolytic viral therapies, offer promising results. However, the effectiveness of these novel approaches requires demonstration in larger clinical trials. A better understanding of the TME and developing combined and personalized TME-targeting treatment protocols may pave the way for breakthroughs in the management and treatment of HGG.

Author Contributions

Conceptualization, E.D., N.Y., and M.K.; methodology, E.D., N.Y., and M.K.; data curation, E.D.; writing—original draft preparation, E.D., D.M., A.S.; writing—review and editing, all; supervision, M.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. The TME niches and molecular landscape of HGG (a) Overview of the TME of glioblastomas, with immunological players, and the three main niches showing a certain presence of specific molecular profiles. (b) The vascular niche: This niche is characterized by pronounced angiogenesis with a correspondingly increased VEGF; tumor macrophages accumulate here. Cytokines such as IL-6 and IL-8 are increased. Likewise, PTEN leads to increased matrix cross-linking proteins, resulting in accelerated angiogenesis. (c) The hypoxic niche contributes to glioma growth and resistance. PTEN is increased, and HIF contributes to the upregulation of VEGF and IL-8 and supports stem cell presence indicated via increased CD133. Via tyrosine hydroxylase activity, inflammatory cytokines are reduced. (d) The invasive niche: This niche is marked by a normal vessel distribution and the transition to normal brain tissue. Stem cells are associated with the vessel structure, glioma cells and microglia go along in tumor growth, and glioma stem cells are associated with endothelial cells via CXCL12/CXCR4. The cellular matrix also supports invasive tumor growth. CD133, CD133–prominin 1, PROM1, is a transmembrane protein; CXCL12. C-X-C motif chemokine ligand 12; CXCR4, C-X-C chemokine receptor type 4; EGFR, epidermal growth factor receptor; HIF-1α, hypoxia-inducible factor 1-alpha; HIF-2α, hypoxia-inducible factor 2-alpha; IL-6, interleukin (6); INFy, interferon gamma; MGMT, O6-methylguanine–DNA methyltransferase; PD-L1, programmed death-ligand 1; PTEN, phosphatase and tensin homolog; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor. Reproduced with permission from Barthel et al. under Creative Commons CC BY License [3].
Figure 1. The TME niches and molecular landscape of HGG (a) Overview of the TME of glioblastomas, with immunological players, and the three main niches showing a certain presence of specific molecular profiles. (b) The vascular niche: This niche is characterized by pronounced angiogenesis with a correspondingly increased VEGF; tumor macrophages accumulate here. Cytokines such as IL-6 and IL-8 are increased. Likewise, PTEN leads to increased matrix cross-linking proteins, resulting in accelerated angiogenesis. (c) The hypoxic niche contributes to glioma growth and resistance. PTEN is increased, and HIF contributes to the upregulation of VEGF and IL-8 and supports stem cell presence indicated via increased CD133. Via tyrosine hydroxylase activity, inflammatory cytokines are reduced. (d) The invasive niche: This niche is marked by a normal vessel distribution and the transition to normal brain tissue. Stem cells are associated with the vessel structure, glioma cells and microglia go along in tumor growth, and glioma stem cells are associated with endothelial cells via CXCL12/CXCR4. The cellular matrix also supports invasive tumor growth. CD133, CD133–prominin 1, PROM1, is a transmembrane protein; CXCL12. C-X-C motif chemokine ligand 12; CXCR4, C-X-C chemokine receptor type 4; EGFR, epidermal growth factor receptor; HIF-1α, hypoxia-inducible factor 1-alpha; HIF-2α, hypoxia-inducible factor 2-alpha; IL-6, interleukin (6); INFy, interferon gamma; MGMT, O6-methylguanine–DNA methyltransferase; PD-L1, programmed death-ligand 1; PTEN, phosphatase and tensin homolog; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor. Reproduced with permission from Barthel et al. under Creative Commons CC BY License [3].
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Figure 2. Molecular pathways implicated in the various TME of HGG. (a) The integrated hypoxic peri-arteriolar niche is a combined concept from the 5 interplayed niches. (b) Interaction between peri-vascular niche and hypoxia/necrotic niche via VEGF, SDF1α, and CXCR4. (c) ECM niche. (d) interaction between immune niche and hypoxia/necrotic niche via HIF1α, HIF2α, lymphocytes, CD8+ T cells, interferon-γ, CD4+ T cells, pSTAT pathway, CCL2, CFS1, macrophages, Foxp3+ Tregs, Th17 cells, TCR, CD4+ type1 Treg, and CD4+ T helper 17. (e) GSC hypoxia/necrotic niche. (f) Interaction between immune niche and peri-arteriolar niche via CD177, MMP9, OPN, and CD68+ macrophages. Reproduced with permission from Shi et al. under Creative Commons CC BY License [7].
Figure 2. Molecular pathways implicated in the various TME of HGG. (a) The integrated hypoxic peri-arteriolar niche is a combined concept from the 5 interplayed niches. (b) Interaction between peri-vascular niche and hypoxia/necrotic niche via VEGF, SDF1α, and CXCR4. (c) ECM niche. (d) interaction between immune niche and hypoxia/necrotic niche via HIF1α, HIF2α, lymphocytes, CD8+ T cells, interferon-γ, CD4+ T cells, pSTAT pathway, CCL2, CFS1, macrophages, Foxp3+ Tregs, Th17 cells, TCR, CD4+ type1 Treg, and CD4+ T helper 17. (e) GSC hypoxia/necrotic niche. (f) Interaction between immune niche and peri-arteriolar niche via CD177, MMP9, OPN, and CD68+ macrophages. Reproduced with permission from Shi et al. under Creative Commons CC BY License [7].
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Figure 3. Interaction between the TME and glioma. The interactions between TME and glioma cells are complex, as the multiple players of widespread origin show. Intracellular factors, pathways, cytokines, genetic alterations, or environmental properties are involved, and the molecular characteristics of glioma cells are dependent on these parameters. Furthermore, the glioma molecular patterns influence the TME composition. 1p19q, combined loss of the short-arm chromosome 1 (i.e., 1p) and the long-arm chromosome 19 (i.e., 19q); ATRX, transcriptional regulator ATRX also known as ATP-dependent helicase ATRX (-mut, mutation); BRAF (human gene that encodes a protein called B-Raf); CCL2, CC-chemokine-ligand-2; CCR2, C–C chemokine receptor type 2; CDK4/6, cyclin-dependent kinase 4 and 6; CD133, CD133–prominin 1, PROM1, is a transmembrane protein; EGFR, epidermal growth factor receptor (vIII, variant III); EVs, extracellular vesicles; IDH1, isocitrate dehydrogenase-(1) (mut, mutation; wt, wild type); IL- family, interleukin family; KIAA1549-BRAAF, KIAA1549 (protein- coding gene); LOX, lysyl oxidase, also known as protein-lysine 6-oxidase; MGMT, O6-methylguanine–DNA methyltransferase; mTOR, mechanistic target of rapamycin; NF1, neurofibromatosis type 1; NF-κB, nuclear factor “kappa-light-chain-enhancer” of activated B-cells; P53, tumor protein P53 or tumor suppressor p53; PD-L1, programmed death-ligand 1; PHD, prolyl hydroxylase domain enzymes; PTEN, phosphatase and tensin homolog; RAS, RAS proteins control signaling pathways that are key regulators of normal cell growth and malignant transformation; RB1, RB transcriptional core- pressor 1; TME, tumor microenvironment; TNF, tumor necrosis fac- tor; WNT, Wnt signaling pathway; antiporter system xc. Reproduced with permission from Barthel et al. under Creative Commons CC BY License [3].
Figure 3. Interaction between the TME and glioma. The interactions between TME and glioma cells are complex, as the multiple players of widespread origin show. Intracellular factors, pathways, cytokines, genetic alterations, or environmental properties are involved, and the molecular characteristics of glioma cells are dependent on these parameters. Furthermore, the glioma molecular patterns influence the TME composition. 1p19q, combined loss of the short-arm chromosome 1 (i.e., 1p) and the long-arm chromosome 19 (i.e., 19q); ATRX, transcriptional regulator ATRX also known as ATP-dependent helicase ATRX (-mut, mutation); BRAF (human gene that encodes a protein called B-Raf); CCL2, CC-chemokine-ligand-2; CCR2, C–C chemokine receptor type 2; CDK4/6, cyclin-dependent kinase 4 and 6; CD133, CD133–prominin 1, PROM1, is a transmembrane protein; EGFR, epidermal growth factor receptor (vIII, variant III); EVs, extracellular vesicles; IDH1, isocitrate dehydrogenase-(1) (mut, mutation; wt, wild type); IL- family, interleukin family; KIAA1549-BRAAF, KIAA1549 (protein- coding gene); LOX, lysyl oxidase, also known as protein-lysine 6-oxidase; MGMT, O6-methylguanine–DNA methyltransferase; mTOR, mechanistic target of rapamycin; NF1, neurofibromatosis type 1; NF-κB, nuclear factor “kappa-light-chain-enhancer” of activated B-cells; P53, tumor protein P53 or tumor suppressor p53; PD-L1, programmed death-ligand 1; PHD, prolyl hydroxylase domain enzymes; PTEN, phosphatase and tensin homolog; RAS, RAS proteins control signaling pathways that are key regulators of normal cell growth and malignant transformation; RB1, RB transcriptional core- pressor 1; TME, tumor microenvironment; TNF, tumor necrosis fac- tor; WNT, Wnt signaling pathway; antiporter system xc. Reproduced with permission from Barthel et al. under Creative Commons CC BY License [3].
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Figure 4. Various targeted therapies directed at the TME of HGG. The targeting of specific areas of the TME in preclinical and clinical trials is shown. Various areas include the activation of effector cells using dendric cell vaccines or oncolytic viruses, targeting genetic lesions, neoantigens, and tumor-associated antigens, inhibition of secretory factors, inhibition of immunosuppressive cells, and immune checkpoint inhibitors. CAR-T: chimeric antigen receptor T cells; DAMP: damage-associated molecular pattern; EGFR: epidermal growth factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; HSP: heat shock protein; IDH1: isocitrate dehydrogenase 1; PAMP: Pathogen-Associated Molecular Patterns; NK cell: natural killer cell; VEGF: vascular endothelial growth factor.
Figure 4. Various targeted therapies directed at the TME of HGG. The targeting of specific areas of the TME in preclinical and clinical trials is shown. Various areas include the activation of effector cells using dendric cell vaccines or oncolytic viruses, targeting genetic lesions, neoantigens, and tumor-associated antigens, inhibition of secretory factors, inhibition of immunosuppressive cells, and immune checkpoint inhibitors. CAR-T: chimeric antigen receptor T cells; DAMP: damage-associated molecular pattern; EGFR: epidermal growth factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; HSP: heat shock protein; IDH1: isocitrate dehydrogenase 1; PAMP: Pathogen-Associated Molecular Patterns; NK cell: natural killer cell; VEGF: vascular endothelial growth factor.
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Table 1. Key regulatory molecules involved in the TME.
Table 1. Key regulatory molecules involved in the TME.
Molecular FactorInteraction
EGFRPromotes glioma cell migration and reduces inflammatory response; induces macrophage infiltration; support neo-angiogenesis; increased in a hypoxic environment
EGFRvIIISupports glioma cell survival, invasion, and stemness; inflammatory triggering properties; increased sensitivity to temozolomide; macrophage infiltration; support neo-angiogenesis
IDHPromotes tumor-infiltrating lymphocytes, with less antitumor T-cell response; higher expression of PD-L1
IDH1mutFavorable response to chemotherapy and radiation; reduced IFN-γ and CD8; less antitumor T-cell response
ATRXMutation: stabilization of the glioma cell; deletion: promotes expression of (type I) interferon
KIAA1549-BRAF fusionBRAF activation promotes pro-cancerogenic senescence via a p16 (INK4a) pathway, pro-cancerogenic TME via the CCL2/CCR2 axis; microglia recruitment
NF1NF1 incompetence: decreased cancer cell homogeneity; enhanced NF1 expression: diminished microglia activity; NF1 deactivation: increased macrophage activation
PTENPTEN mutation: immunosuppressive TME, PDL-1 enhancement; PTEN absences/deficiency: immune resistance, increased T-cell apoptosis, promoting cross-linking of proteins; supports VEGF
MGMTHypermethylation: better therapy response, promoted by hypoxic TME; reduced in presence of decreased Wnt-signaling; methylations seem to influences immune response
p53Dysfunction: cell invasion and migration of glioma cells and supports inflammatory processes; loss: pro-cancerogenic activities of SASP, resulting in immunosuppressive TME; activation: immune invigoration
CDK4/6Dysfunction: promotes phosphorylation of RB1, resulting in glioma cells’ division; lack of CDK4; prevents glioma cell development
RB1Mutation: increased glioma cell proliferation rate
HIFUpregulation of VEGF and IL-8; support stem cell presence; reduction of IFN-y and TNF
EGFR, epidermal growth factor receptor (vIII, variant III); IDH1, isocitrate dehydrogenase-(1) (mut, mutation; wt, wild type); ATRX, transcriptional regulator ATRX also known as ATP-dependent helicase ATRX (-mut, mutation); KIAA1549-BRAAF, KIAA1549 (protein-coding gene); NF1, neurofibromatosis type 1; PTEN, phosphatase and tensin homolog; MGMT, O6-methylguanine–DNA methyltransferase; p53, tumor protein P53 or tumor suppressor p53; CDK4/6, cyclin-dependent kinase 4 and 6; RB1, RB transcriptional corepressor 1; HIF, hypoxia-inducible factor. Reproduced with permission from Barthel et al. under Creative Commons CC BY License [3].
Table 2. Selected pivotal research studies involving immunotherapy trials in HGG.
Table 2. Selected pivotal research studies involving immunotherapy trials in HGG.
ApproachPhaseCompleted/OngoingSample SizePFS (m)OS (m)Year PublishedReferences
Adaptive T cells
CAR-T cells (IL13Rα2)ICompleted3NR112015NCT00730613
Assessment of the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded autologous CD8-positive T-cell clones genetically modified to express the IL-13 zetakine chimeric immunoreceptor and the Hy/TK selection/suicide fusion protein in patients with recurrent or refractory, high-grade malignant glioma.
T cells (HER2-CAR-CMV)ICompleted163.524.52017NCT01109095
Evaluation of the safety of escalating doses of autologous CMV-specific cytotoxic T-lymphocytes (CTL) genetically modified to express chimeric antigen receptors targeting the HER2 molecule in patients with HER2-positive glioblastoma multiforme, who have recurrent or progressive disease after front line therapy.
T cells (CMV specific)ICompleted198.213.32014ACTRN12609000338268
Assessment of the safety and tolerability of autologous CMV-specific T-cell therapy for recurrent GBM.
Immuncell-LC-T cellsIIICompleted1808.122.52017NCT00807027
Assessment of the superiority of INNOCELL Corp. “Immuncell-LC” in aspects of therapeutic efficacy and safety when administered with temozolomide to glioblastoma patients when compared with the control group who did not receive administration of the drug.
Checkpoint inhibitors
Ipilimumab (BMS-734016)IICompleted72NR7/42012NCT00623766
Assessment of the response of melanoma with brain metastases to ipilimumab treatment while maintaining acceptable tolerability.
Nivolumab, anti-PD-1 antibodyIIICompleted 369 1.59.8 2020NCT02017717
Comparison of the efficacy and safety of nivolumab administered alone versus bevacizumab in patients diagnosed with recurrent; evaluation of the safety and tolerability of nivolumab administered alone or in combination with ipilimumab in patients with different lines of GBM therapy (CheckMate143).
Nivolumab, anti-PD-1 antibodyIIICompleted (last update posted: 3 March 2023) NR NRNRNRNCT02617589
Evaluation of patients with glioblastoma that is MGMT unmethylated (the MGMT gene is not altered by a chemical change). Comparison with patients receiving standard therapy with temozolomide in addition to radiation therapy (CheckMate498).
Nivolumab, anti-PD-1 antibodyIIICompleted 71610.628.92022NCT02667587
Evaluation of patients with glioblastoma that is MGMT methylated (the MGMT gene is altered by a chemical change). Patients will receive temozolomide plus radiation therapy. They will be compared to patients receiving nivolumab in addition to temozolomide plus radiation therapy (CheckMate548).
Vaccines
IMA950-vacICompleted45NR15.32016NCT01222221
The aim of the study was to elucidate the side effects of vaccine therapy when administered together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma multiforme.
DCs vaccineIICompleted2612.723.42017NCT01006044
Investigation of efficacy and safety of autologous dendritic cell vaccination in glioblastoma multiforme patients after complete surgical resection with a fluorescence microscope.
CDX-110 (rindopepimut)IIICompleted745820.12017NCT01480479
Investigation whether an adding of the experimental vaccine rindopepimut (also known as CDX-110) to the commonly used chemotherapy drug temozolomide can help improve the life expectancy of patients with newly diagnosed, resected EGFRvIII positive glioblastoma. CDX-110 was admixed with granulocyte macrophage-colony stimulating factor.
CDX-110 (rindopepimut)IICompleted855.521.82015NCT00458601
Evaluation of CDX-110 vaccination when provided with standard care treatment in glioblastoma (maintenance temozolomide therapy). Study treatment was given until disease progression. Follow-up for long-term survival information. Efficacy was measured by the progression-free survival status at 5.5 months from the date of the first dose. CDX-110 was admixed with Granulocyte macrophage-colony stimulating factor.
Dendritic cell (DC)-based vaccine (targeting cancer stem cells)ICompleted2023.125.52013NCT00846456
Evaluation of immunological response, time to disease progression and survival time (time frame: five years) in patients with glioblastoma.
GP96 heat shock protein-peptide complexI/IICompleted414.59.52014NCT00293423
Investigation of the side effects and best dose of gp96 heat shock protein–peptide complex vaccine to see how well it worked in treating patients with recurrent or progressive high-grade glioma over time.
Survivin peptide mimic SurVaxM (SVN53-67/M57-KLH)ICompleted917.686.62016NCT01250470
Study of the side effects of vaccine therapy when given together with sargramostim in treating patients with malignant glioma.
Cytomegalovirus pp65-targeted vaccinationI/IICompleted1125.341.12015; 2017NCT00639639
Study of how well vaccine therapy worked in treating patients with newly diagnosed glioblastoma multiforme recovering from lymphopenia caused by temozolomide.
GVAX vaccineICompleted11NR8.82016NCT00694330
The aim was to test the safety of vaccination of cells called GM-K562 cells mixed with the participant’s own irradiated tumor cells in glioblastoma. GM-K562 is a granulocyte-macrophage colony stimulating factor producing cell line.
DCVax®-LIIICompleted331NR34.7/19.82018; 2023NCT00045968; NCT02146066
Investigation of the efficacy of an investigational therapy called DCVax(R)-L in patients with newly diagnosed GBM for whom surgery was indicated (NCT00045968).
Open-label expanded access to study for patients for whom the vaccine was manufactured during the Northwest Biotherapeutics’ 020,221 DCVax-L for GBM screening process; however, they subsequently failed to meet specific enrollment criteria (NCT02146066).
NOA-16ICompleted39NRNR2021NCT02454634
Evaluation of safety and tolerability of and immune response to the IDH1 peptide vaccine in patients with IDH1R132H-mutated, WHO grade III–IV gliomas.
DNX-2401 (formerly known as delta-24-RGD-4C)I/ICompleted 37NR9.52018NCT00805376
The aim was to find the highest tolerable dose of DNX-2401 that can be injected directly into brain tumors and into the surrounding brain tissue where tumor cells can multiply. A second goal was to study how the new drug DNX-2401 affects brain tumor cells and the body in general.
Personalized neoantigen cancer-vaccine-wRTI/IbRecruiting (last update posted: 28 May 2024)NRNRNRNRNCT02287428
Study of a new type of vaccine as a possible treatment for patients with glioblastoma. It tested the safety of an investigational intervention and tried to define the appropriate dose of the intervention to use for further studies.
PVSRIPOI/IICompleted61NR 12.52018NCT01491893
The aim iwas to determine the maximally tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PVSRIPO when delivered intracerebrally by convection-enhanced delivery (CED)
ACTRN, Australian clinical trials registration number; CMV, cytomegalovirus; DCs, dendritic cells; EGFR: epidermal growth factor receptor (vIII: variant III); GBM: glioblastoma multiforme; GVAX, cancer vaccine composed of whole tumor cells; HSPPC-96, heat shock protein–peptide complexes 96; IDH, isocitrate dehydrogenase; MGMT, O6-methylguanine–DNA methyltransferase; NCT, ClinicalTrials.gov Identifier; NR: not reported, OSm, overall survival (m, months); PFSm, progression-free survival (m, months); PVSRIPO, modified poliovirus. The status of the studies was last checked on 28 September 2021 (https://clinicaltrials.gov/). Adapted with permission from Barthel et al. under Creative Commons CC BY License [3].
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Demir, E.; Montgomery, D.; Saloum, A.; Yaghi, N.; Karsy, M. Current Understanding Regarding the Glioma Microenvironment and Impact of the Immune System. Neuroglia 2025, 6, 13. https://doi.org/10.3390/neuroglia6010013

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Demir E, Montgomery D, Saloum A, Yaghi N, Karsy M. Current Understanding Regarding the Glioma Microenvironment and Impact of the Immune System. Neuroglia. 2025; 6(1):13. https://doi.org/10.3390/neuroglia6010013

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Demir, Enes, Deondra Montgomery, Ammar Saloum, Nasser Yaghi, and Michael Karsy. 2025. "Current Understanding Regarding the Glioma Microenvironment and Impact of the Immune System" Neuroglia 6, no. 1: 13. https://doi.org/10.3390/neuroglia6010013

APA Style

Demir, E., Montgomery, D., Saloum, A., Yaghi, N., & Karsy, M. (2025). Current Understanding Regarding the Glioma Microenvironment and Impact of the Immune System. Neuroglia, 6(1), 13. https://doi.org/10.3390/neuroglia6010013

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