image: (A) Resident microglia are polarized toward a pro-tumorigenic state, often mediated by glioma-derived factors like Versican. These cells facilitate tumor progression by MMP14 and STI1, SPP1, and EGF. They also contribute to the immunosuppressive niche through the expression of PD-L1 and TGF-β. (B) Circulating monocytes are recruited in glioma via the CCL2/CCR2 and CSF1/CSF1R signaling axes. Once infiltrated, they differentiate into tumor-associated macrophages. These cells exhibit a functional spectrum: while some maintain pro-inflammatory roles (secreting IL-1β, IL-27, and TNF), the majority adopt an anti-inflammatory and immunosuppressive phenotype characterized by high expression of PD-L1, TGF-β, IL-10, and ARG1. Tumor-associated macrophages also drive angiogenesis through VEGF/EGF and remodel ECM via MMP2. (C) Neutrophils are recruited to glioma via IL-8 signaling. Neutrophils promote the further infiltration of themselves and monocytes to glioma TME. They also promote an immunosuppressive niche by expressing ARG1. Specially, "hybrid" dendritic-like neutrophils may possess anti-tumoral potential by priming T-cell cytotoxicity and memory responses. (D) MDSCs are recruited from the circulation via CCL2 and stromal cell-derived factor 1α (SDF-1α). MDSCs are potent inhibitors of T cell activity, utilizing ARG1, inducible nitric oxide synthase (iNOS), PD-L1, and TGF-β to stifle the adaptive immune response. (E) The glioma TME actively impairs the "sentinel" function of DCs. Glioma-derived factors, including VEGF, IL-6, and IL-10, inhibit the maturation and antigen-presentation capabilities of DCs, preventing the effective priming of anti-tumor T cells. (F) The adaptive immune arm is characterized by a "highly immunosuppressive state." T cells undergo exhaustion or apoptosis following interactions between PD-1 and PD-L1. The upregulation of TGF-β and IDO1 further suppresses T cell activity. (G) Glioma cells form functional synapses with neurons, hijacking neurotransmitters such as Glutamate and GABA to drive tumor progression. Neurotrophic factors, including NLGN3, BDNF, IGF1, and SEMA4F, provide essential growth-promoting signals to the tumor cells. (H) Reactive astrocytes communicate with glioma cells through gap junctions. Glioma cells also communicate with astrocytes through IL-11/IL11RA and ANXA1/FRR1 axes to suppress T cell immunity. (I) Endothelial cell-derived VEGF and FGF stimulate angiogenesis and promote tumor growth. The vasculature is often structurally compromised, leading to blood-brain barrier (BBB) disruption. This facilitates the infiltration of peripheral immune cells but also results in poor drug delivery. (J) Lymphatic endothelial cells interact with tumor cells via the CCL21/CCR7 axis to promote tumor growth. ANXA1, annexin A1; FRR1, fragile site-related protein 1; ARG1, arginase 1; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; CCL2, C-C motif chemokine ligand 2; CCL21, C-C motif chemokine ligand 21; CCR2, C-C motif chemokine receptor 2; CCR7, C-C motif chemokine receptor 7; CSF1, colony-stimulating factor 1; CSF1R, colony-stimulating factor 1 receptor; CXCR4, C-X-C motif chemokine receptor 4; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast growth factor; GABA, gamma-aminobutyric acid; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; IDO1, indoleamine 2,3-dioxygenase 1; IGF1, insulin-like growth factor 1; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-11, interleukin-11; IL-27, interleukin-27; IL11RA, interleukin-11 receptor subunit α; iNOS, inducible nitric oxide synthase; MDSCs, myeloid-derived suppressor cells; MMP2, Matrix metalloproteinase-2; MMP14, Matrix metalloproteinase-14; NF-κB, nuclear factor kappa B; NLGN3, neuroligin-3; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; p-STAT, phosphorylated signal transducer and activator of transcription; SDF-1α, stromal cell-derived factor 1 α; SEMA4F, semaphorin 4F; SPP1, secreted phosphoprotein 1; STI1, stress-inducible protein 1; TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
Credit: Chinese Medical Journal
The prognosis for glioma patients remains extremely poor despite aggressive multimodal standard therapy: maximal safe resection, radiotherapy, and temozolomide chemotherapy, with median survival rarely exceeding 15 to 18 months. Why are conventional treatments so limited? Recent scientific advances point to a fundamental cause: therapeutic resistance arises not only from the intrinsic heterogeneity of tumor cells but also from a long-overlooked “tumor microenvironment (TME) ecosystem.”
Within this ecosystem, resident microglia and recruited macrophages are not passive bystanders but are actively “educated” by the tumor to become pillars of immunosuppression. They construct a barrier that disables adaptive immunity, creating a paradox of “inflammation without immunity,” in which infiltrating lymphocytes are often rendered exhausted and dysfunctional. Beyond immune dysregulation, glioma progression relies on deep interactions with non-immune components of the central nervous system. Groundbreaking studies show that neurons form functional excitatory synapses with glioma cells, driving tumor growth through neurotransmitter release (e.g., glutamate). This activity-dependent growth embeds tumor cells within neural circuits, creating a feed-forward loop. Simultaneously, other brain cells are co-opted: reactive astrocytes enhance invasion via gap junctions and secreted factors while fostering an immunosuppressive niche; Cells of the oligodendrocyte lineage are manipulated to support tumor angiogenesis and immune evasion. Additionally, glioma-induced vascular remodeling results in a leaky and disorganized vascular network that, while fueling tumor metabolism, severely hampers drug delivery.
Thus, the glioma TME acts as both the central conductor of therapeutic failure and an unprecedented source of therapeutic opportunity. The old paradigm of targeting cancer cells alone is shifting toward a more nuanced strategy: disrupting neuron‑tumor communication and reprogramming the immune landscape from suppressive to antitumor states.
This review synthesizes the latest advances in decoding the multilayered glioma TME, with special emphasis on stromal-glioma crosstalk and myeloid cell plasticity, to provide a conceptual framework for next-generation therapies. It marks a fundamental shift in glioma therapeutics: the future battlefield lies in dismantling the entire tumor-supporting ecosystem, not merely eliminating malignant cells-offering new hope in the fight against this devastating disease.
Reference
Title of original paper: Glioma Microenvironment: Cellular Crosstalk, Immunosuppression, and Novel Therapeutic Perspectives
Journal: Chinese Medical Journal
DOI: https://doi.org/10.1097/CM9.0000000000004151
About Linjie Zhao from Sichuan University
Dr. Linjie Zhao is a Professor and Principal Investigator (Doctoral Supervisor) in the Department of Neurosurgery at West China Hospital, Sichuan University, and the State Key Laboratory of Biotherapy. He received the NSFC Excellent Young Scientist Fund (Overseas) and the Sichuan Tianfu Emei Plan for Young Talents. His research focuses on the glioma immune microenvironment and targeted therapies. Dr. Zhao has published in Cancer Cell and Cancer Discovery, with findings cited in Nature, Nature Reviews Cancer, and Nature Reviews Drug Discovery. He serves on the editorial boards of Science Bulletin, Oncogene, and Phenomics and holds leadership positions in neuro-oncology organizations.
Funding information
This work was supported by National 2030 Projects of Scientific and Technological Innovation (2023ZD0500300), National Natural Science Foundation of China (82473052) and the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYYC24007) to Linjie Zhao.
Journal
Chinese Medical Journal
Method of Research
Literature review
Subject of Research
Not applicable
Article Title
Glioma Microenvironment: Cellular Crosstalk, Immunosuppression, and Novel Therapeutic Perspectives
Article Publication Date
15-Jun-2026
COI Statement
None