Glioma-derived extracellular vesicles as drivers of immunotherapeutic resistance: mechanisms of immune reprogramming and metabolic intervention.

Gliomas, particularly glioblastoma (GBM), secrete abundant extracellular vesicles (EVs) that function as critical mediators of intercellular communication within the tumor microenvironment. These EVs carry diverse bioactive cargoes-including immune checkpoint proteins, non-coding RNAs, metabolites, and metabolic regulators-and can traverse the blood-brain barrier, potentially through endothelial uptake, transcytosis, and glioma-associated barrier remodeling, thereby linking local and systemic immune regulation. This review summarizes current knowledge regarding the mechanisms by which glioma-derived EVs contribute to immunotherapeutic resistance. EV-associated programmed death-ligand 1 (PD-L1) directly engages PD-1 on T cells and may exert broader and more sustained immunosuppressive effects than tumor cell membrane-bound PD-L1 by enabling distal immune modulation and multivalent inhibitory signaling. Glioma-derived EVs also promote myeloid-derived suppressor cell expansion, drive tumor-associated macrophage and microglial polarization toward immunosuppressive phenotypes, impair dendritic cell-mediated antigen presentation, and collectively reinforce T-cell dysfunction. In addition, EV-enriched non-coding RNAs, such as miR-25-3p, miR-3591-3p, and lncRNA H19, regulate PI3K-AKT-mTOR, JAK2/STAT3, and related pathways to promote myeloid reprogramming, immune escape, and temozolomide resistance. Importantly, EV-mediated temozolomide resistance and immunotherapeutic resistance may be interconnected through shared mechanisms involving non-coding RNA transfer, metabolic remodeling, inhibitory cytokine signaling, and myeloid-driven immune suppression. Furthermore, glioma EVs participate in tumor-specific immunometabolic regulation, including lipid, adenosine, amino acid, and glycolytic pathways, while exerting context-dependent effects on antigen presentation by either suppressing dendritic cell maturation or, under certain conditions, functioning as antigen carriers to stimulate antitumor immunity. Collectively, glioma-derived EVs act as central organizers of immune escape and therapeutic resistance. Targeting EV biogenesis, release, uptake, or specific immunosuppressive cargoes may provide promising opportunities to overcome resistance and improve immunotherapy for glioma. Future studies should focus on deciphering EV-mediated immune regulatory networks, identifying robust glioma-specific EV biomarkers, standardizing EV detection platforms, and developing precision EV-based therapeutic strategies.