Advancing chimeric antigen receptor T-cell therapy frontiers in glioblastoma: Navigating the current landscape from clinical hurdles to breakthrough strategies.

Abstract

Glioblastoma (GBM) is a lethal brain tumor with poor outcomes under standard therapies, and its rising global incidence underscores the urgent need for novel treatments. Chimeric antigen receptor T (CAR-T) cell therapy holds promise for GBM but faces unique challenges, including antigenic heterogeneity, a profoundly immunosuppressive tumor microenvironment (TME), limited trafficking across the blood brain barrier (BBB), and inadequate persistence. This comprehensive review provides an integrated perspective on emerging CAR-T strategies for GBM, systematically outlining ongoing and completed trials. It integrates innovative advances in multi-antigen targeting approaches such as bivalent, tandem, and multi-specific CAR constructs, as well as logic-gated designs that enhance tumor specificity and mitigate antigen escape. Further, we discuss advanced CAR engineering innovations such as armored cytokine-secreting constructs, metabolic reprogramming, and next-generation allogeneic platforms, including induced pluripotent stem cell (iPSC) derived CAR-T cell technologies aiming for durability, improvement and scalability. In parallel, novel delivery methods such as locoregional administration, nanoparticle/focused-ultrasound BBB modulation, and biomaterial scaffolds are also explored alongside rational combination approaches with checkpoint inhibitors and oncolytic virus. Collectively, this integrated perspective defines a translational roadmap for next generation CAR-T therapies, with the potential to achieve durable and clinically meaningful responses in GBM.