Unraveling the glioblastoma (GBM) tumor microenvironment: future perspective on targeted immunotherapy.

Glioblastoma (GBM) is one of the most aggressive, fast-growing, and therapeutically challenging brain tumors. The difficulty in managing GBM stems from its genetic instability and the intricately complex tumor microenvironment (TME). Within the TME, intricate interactions between neoplastic cells and signaling mediators drive tumor progression. Despite advances in current treatments, obstacles such as the blood-brain barrier (BBB) and pronounced inter- and intratumoral heterogeneity continue to hinder therapeutic success. Consequently, research efforts have increasingly focused on immunotherapeutic strategies that combine immune checkpoint inhibitors (ICIs) with standard-of-care (SOC) treatments or other immune-remodeling modalities, which seek to reprogram the tumor landscape and restore robust, durable anti-tumor responses. In this context, chemoradiation and oncolytic viruses induce immunogenic cell death and activate innate immunity, creating opportunities for checkpoint inhibitors to amplify T-cell responses. Complementing these strategies, engineered CAR-T cells and myeloid-targeting agents address tumor antigen loss and macrophage-mediated suppression of the immune response. Together, by targeting these complementary resistance mechanisms, combination regimens hold the potential to transform the immunologically 'cold' GBM TME into an inflamed and treatment-responsive state. Collectively, these combinatorial approaches converge to remodel the GBM microenvironment, enhancing dendritic cell (DC) activation, promoting T-cell infiltration, and thereby promoting durable anti-tumor immunity, as well as extending survival. This review provides a comprehensive analysis of the TME's role in GBM progression, highlighting the latest immunotherapeutic advances designed to address TME-related obstacles and enhance therapeutic efficacy and patient survival.