CAR-T Cell Therapy for Glioblastoma: Obstacles and Advances.
Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising therapeutic potential against GBM, yet its efficacy remains constrained by multiple barriers, including physical barriers imposed by the blood-brain barrier and extracellular matrix, the immunosuppressive tumor microenvironment, spatiotemporal antigen heterogeneity, and safety concerns. In this review, we summarize the major obstacles limiting CAR-T therapy in GBM and discuss emerging strategies to overcome these challenges. Next-generation engineered CAR-T cells-through armored modifications, logic-gated regulation, and dual-targeting approaches-enhance specificity, persistence, and controllability. Concurrently, combinatorial approaches leveraging biomaterials enable localized delivery and sustained release of CAR-T cells, while physical modalities, such as focused ultrasound and thermal modulation, can transiently disrupt the blood-brain barrier or induce immunogenic cell death. Integration with real-time imaging further enables dynamic monitoring of therapeutic responses. Together, these synergistic strategies may enhance antitumor efficacy while minimizing systemic toxicity, paving the way for future CAR-T-based therapies in glioblastoma.