Extracellular Vesicles in Glioma: From Tumor Microenvironment Reprogramming to Liquid Biopsy and Therapeutic Translation

Gliomas remain refractory to contemporary neurosurgical and adjuvant therapies due to diffuse infiltration, immune evasion, and rapid development of therapeutic resistance. Extracellular vesicles (EVs), lipid-encapsulated substrates of various sizes that carry nucleic acid or proteins, are now recognized as central regulators of tumor–immune crosstalk and a potential unifying mechanism linking microenvironmental reprogramming with disease progression. Glioma-derived EVs function as active signaling platforms that remodel the tumor microenvironment. EV cargo—including PD-L1, TGF-β, and regulatory microRNAs—suppresses cytotoxic T-cell function, promotes M2 macrophage polarization, and impairs dendritic cell antigen presentation, collectively reinforcing an immunosuppressive niche. Additionally, EV-mediated transfer of resistance-associated cargo contributes to chemoresistance and radioresistance, representing key paracrine mechanisms of treatment failure. EV-associated nucleic acids specifically have enabled detection of alterations such as EGFRvIII, IDH1 mutations, and MGMT promoter methylation in early clinical studies. These findings support EV-based liquid biopsy as a promising approach for minimally invasive molecular characterization and disease monitoring. However, most mechanistic and therapeutic evidence remains preclinical, while clinical studies are limited by small cohorts, heterogeneous EV isolation and characterization methods, and a lack of prospective validation. Ultimately, EVs represent a biologically important interface between glioma biology and the immune microenvironment, with emerging applications in disease monitoring and therapeutic development. Prospective validation and technical standardization remain essential to enable clinical translation.