Engineering next-generation CAR-T cells for glioblastoma treatment: a review of innovations in receptor design, antigen targeting, and therapeutic persistence.

Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults and is characterized by poor prognosis, profound intratumoral heterogeneity, and a highly immunosuppressive tumor microenvironment (TME). Although chimeric antigen receptor (CAR)-T cell therapy has shown remarkable efficacy in hematologic malignancies, clinical responses in GBM remain inconsistent and rarely durable. This review critically evaluates how receptor architecture, antigen selection, multi-antigen targeting, TME- and exhaustion-resistant engineering, locoregional delivery, alternative CAR-cell platforms and computational design address the major biological and anatomical barriers of GBM. What should be given a particular attention is not only the translational gap between preclinical activity and limited clinical efficacy, but also differences in target specificity, antigen escape, safety, delivery route and CAR-T persistence. However, the available evidence indicates that no single engineering strategy is sufficient to overcome the interconnected barriers. The strongest approach is likely to combine several strategies. These should improve antigen coverage, maintain CAR-T cell function, increase safety and improve delivery within the CNS. Future progress in GBM CAR therapy will therefore depend on combining complementary solutions rather than improving only one CAR feature.