Rewiring the Glioma Ecosystem: Glial–Tumor Crosstalk, Immune Evasion, and Therapeutic Opportunities

Glioblastoma (GBM), classified as grade 4 of high-grade glioma (HGG) under the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors (WHO CNS-2021), is the most aggressive primary brain tumor in adults. However, with maximal surgical resection, concurrent radiotherapy, and temozolomide (TMZ) chemotherapy, a median patient survival is still between 14 and 16 months. The persistent failure of current treatments is not only traceable to the molecular complexity of tumor cells but is fundamentally shaped by the tumor microenvironment (TME), in which non-neoplastic cells collectively constitute up to half of the total tumor mass. Reactive astrocytes, microglia, tumor-associated macrophages (TAMs), and oligodendrocyte precursor cells (OPCs) are no longer regarded as passive bystanders but as active architects of tumor progression, immune evasion, and therapy resistance. In this comprehensive review, we systematically describe the molecular mechanisms of glial–tumor crosstalk across all three major glial cells. Reactive astrocytes sustain tumor invasion and chemoresistance through connexin-43 gap junctions, bidirectional IL-6/JAK-STAT3 paracrine signaling, and extracellular vesicle-mediated oncogenic reprogramming. Microglia and TAMs undergo profound transcriptional reprogramming via PI3K/Akt/mTOR and CSF-1R signaling, adopting immunosuppressive states that exclude cytotoxic T cells, maintain glioma stem cell (GSC) niches, and drive angiogenesis. OPCs are now underexplored, accumulate at the tumor border, and cooperate with macrophages via Notch and Wnt/β-catenin pathways to establish a therapy-resistant GSC niche at the precise site of post-surgical recurrence. We further address glial–glial interactions as an independent regulatory layer and integrate recent spatial transcriptomic (ST) results revealing a structured, multi-glial niche that governs drug penetration. Finally, we critically evaluate emerging therapeutic strategies targeting these glial–tumor interfaces, including CSF-1R inhibitors, STAT3 modulators, CD47/SIRPα blockades, and engineered extracellular vesicle-based delivery systems. Understanding and targeting the glial ecosystem is an inseparable new field to explore.