Immune checkpoint blockade in glioblastoma: overcoming barriers through mechanism-informed, biomarker-guided, and combinatorial immunotherapies targeting the tumor microenvironment and validated by clinical trials

Abstract Glioblastoma (GBM), the most aggressive and lethal primary brain tumor in adults, continues to resist conventional therapeutic approaches, with median survival remaining dismally low. Immune checkpoint inhibitors (ICIs), which have revolutionized the treatment of several solid tumors, have shown limited efficacy in GBM owing to the highly immunosuppressive and heterogeneous microenvironment of the tumor. The unique immune landscape of the central nervous system (CNS), characterized by low immunogenicity, restricted T-cell infiltration, and an abundance of regulatory and myeloid-derived suppressor cells, poses considerable barriers to effective immune reactivation. This review provides a comprehensive synthesis of the mechanistic barriers undermining ICI efficacy in GBM, including the blood–brain barrier, low tumor mutational burden, adaptive immune resistance, and iatrogenic immunosuppression. It also explores emerging predictive and prognostic biomarkers, such as programmed death-ligand 1 (PD-L1) expression, immune gene signatures, tumor-infiltrating lymphocyte profiles, and circulating markers in cerebrospinal fluid and plasma, which hold promise for guiding patient selection and therapeutic monitoring. Importantly, recent breakthroughs in combinatorial immunotherapy strategies are highlighted, including the integration of ICIs with radiotherapy, anti-angiogenic agents, oncolytic viruses, personalized neoantigen vaccines, and tumor microenvironment reprogramming approaches. Innovative delivery platforms, such as nanoparticles, focused ultrasound, and convection-enhanced delivery, are also discussed for their potential to improve drug bioavailability and local immune activation in the CNS. This review hypothesizes that the therapeutic efficacy of ICIs in GBM can be considerably enhanced by disrupting immune exclusion and reversing immunosuppression through integrated, multimodal strategies guided by dynamic biomarker profiling and spatially resolved immune mapping. This hypothesis-driven approach aims to bridge translational gaps and inform next-generation clinical trial designs that may unlock the potential of immunotherapy for GBM.