Reconceptualizing glioblastoma immunotherapy: a four-pillar framework to overcome multidimensional resistance

Glioblastoma (GBM) remains a recalcitrant primary brain malignancy characterized by a profound immunosuppressive tumor microenvironment (TME), low mutational burden, and extreme molecular heterogeneity. Despite transformative successes in other solid tumors, clinical efficacy in GBM remains modest due to multifaceted barriers, including impaired antigen presentation, dominant myeloid suppression, and the restrictive blood-brain barrier (BBB). This review provides a comprehensive synthesis of the immunotherapeutic landscape, encompassing checkpoint blockade, vaccines, oncolytic virotherapy, and adoptive cellular therapies. Diverging from traditional modality-centric descriptions, we propose an integrated framework organized around four core pillars of antitumor immunity: enhancing antigen presentation, reversing T cell dysfunction, reprogramming the suppressive TME, and engineering effective intracranial delivery. We detail mechanistic rationales and prioritize recent clinical breakthroughs, including bispecific T-cell engagers and the 2024-2025 milestones in bivalent and TEAM-CAR T cell designs. By delineating mechanisms of resistance and identifying areas of therapeutic convergence, we aim to outline research priorities to render the "cold" GBM niche permissive to durable antitumor immunity.