Decoding immunotherapy resistance in glioblastoma: mechanistic limitations, clinical trial failures, and strategic roadmaps for next-generation checkpoint modulation

Abstract Glioblastoma (GBM) remains one of the most treatment-refractory malignancies, characterized by profound intratumoral heterogeneity, an immunologically “cold” microenvironment, and rapid adaptive resistance to immune checkpoint inhibition. Despite mechanistic advances targeting PD-1, PD-L1, and CTLA-4 pathways, clinical trials have failed to demonstrate meaningful survival benefit, underscoring the multifactorial barriers to immunotherapeutic efficacy. Emerging evidence implicates tumor-intrinsic mechanisms such as antigenic loss, metabolic competition, and epigenetic fixation of T-cell exhaustion alongside extrinsic factors including myeloid-driven immunosuppression, aberrant stromal signaling, and disrupted neuroimmune crosstalk. Moreover, conventional trial designs have inadequately captured spatial and temporal immune dynamics, contributing to translational disconnects. This review critically deconstructs the mechanistic bottlenecks and clinical failures of checkpoint-based strategies in GBM, while delineating integrative roadmaps for next-generation interventions. These include rational combinatorial regimens coupling checkpoint blockade with oncolytic, epigenetic, and metabolic reprogramming therapies; biomarker-informed patient stratification; and adaptive trial architectures. Collectively, this analysis emphasizes the need for precision immuno-oncology paradigms to surmount GBM’s intrinsic and microenvironmental resistance networks.