The Immunosuppressive Microenvironment of Glioblastoma: Mechanisms, Clinical Challenges and Future Directions

Glioblastoma (GBM) remains highly lethal due to intrinsic and extrinsic mechanisms, of which the immunosuppressive tumour microenvironment (TME) collectively limits treatment efficacy. This review synthesises recent advances in understanding how metabolic reprogramming, epigenetic remodelling and immune cell dysfunction converge to establish a stable immunosuppressive network dominated by tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells and exhausted T cells. We further summarise emerging therapeutic strategies, including myeloid-targeting agents, epigenetic modulators, metabolic inhibitors and combination immunotherapy, and discuss their clinical potential in overcoming GBM immune resistance. These insights provide a mechanistic and translational framework for developing next-generation multimodal treatment approaches.