CAR-T cell therapy in glioblastoma: from αβ to γδ T-cell platforms

Glioblastoma multiforme (GBM) remains a highly aggressive brain tumor with limited treatment options and poor survival. The persistent clinical failure has driven interest in novel, immune-based strategies with higher specificity and greater cytotoxic potency, among which chimeric antigen receptor (CAR)-T-cell therapy has emerged as a leading approach. alpha beta CAR-T cells demonstrate safety but limited efficacy due to antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and restricted trafficking to the central nervous system (CNS). gamma delta CAR-T cells, combining innate major histocompatibility complex (MHC)-independent tumor recognition with engineered antigen specificity, have demonstrated preclinical cytotoxicity and features consistent with intratumoral persistence in selected models, as well as off-the-shelf potential, making them a next-generation immunotherapy strategy for GBM.