The immunosuppressive tumor microenvironment in glioblastoma.

Glioblastoma (GBM) remains one of the most lethal primary brain tumors, with limited therapeutic improvement despite maximal surgical resection, radiotherapy, and temozolomide. A major barrier to durable treatment response is the profoundly immunosuppressive tumor microenvironment, which is characterized by immune exclusion, defective antigen presentation, myeloid dominance, and severe T-cell dysfunction. Tumor-associated macrophages, resident microglia, myeloid-derived suppressor cells, neutrophils, regulatory T cells, and glioma-derived extracellular vesicles collectively establish a suppressive niche through cytokine signaling, metabolic restriction, checkpoint ligand expression, impaired phagocytosis, and extracellular matrix remodeling. Key pathways, including TGF-β/SMAD, IL-10/STAT3, IDO-kynurenine metabolism, arginase-1-mediated amino acid depletion, adenosine signaling, hypoxia-HIF-1α activation, and VEGF-driven vascular dysfunction, converge to prevent effective antitumor immunity. This review summarizes the cellular and molecular mechanisms underlying immune suppression in GBM and discusses emerging therapeutic strategies, including myeloid reprogramming, phagocytosis checkpoint blockade, neutrophil and NET targeting, cellular immunotherapy, checkpoint blockade combinations, and metabolic intervention. Understanding these interconnected barriers may guide rational multimodal strategies to convert immune-excluded GBM into immune-responsive disease.