CAR-T Cell Therapy in Glioblastoma: Overcoming Immunological Barriers and Advancing Clinical Translation

Chimeric antigen receptor (CAR) T-cell therapy has delivered unprecedented clinical benefit in hematological malignancies, yet its successful translation to solid tumors remains a major unmet clinical challenge. Glioblastoma (GBM), the most aggressive primary brain tumor, exemplifies the barriers confronting cellular immunotherapy, including profound intratumoral heterogeneity, antigenic escape, a highly immunosuppressive tumor microenvironment, and anatomical constraints imposed by the blood-brain barrier. Together, these features limit CAR-T cell trafficking, persistence and sustained antitumor activity in the central nervous system.In this Review, we examine recent advances in next-generation CAR-T engineering strategies aimed at overcoming these obstacles in GBM. Key developments include multi-antigen and logic-gated CAR designs to mitigate tumor immune evasion, armored CAR-T cells capable of cytokine delivery or resistance to suppressive mediators such as TGF-β, and checkpoint-resistant constructs to counteract functional exhaustion. We also highlight emerging delivery paradigms - including locoregional administration, viral vectors and nanotechnology-enabled platforms - designed to enhance blood-brain barrier penetration and intratumoral retention. Furthermore, we discuss combinatorial strategies integrating CAR-T therapy with immune checkpoint blockade, oncolytic virotherapy and other immunomodulatory interventions to remodel the hostile glioblastoma microenvironment and amplify therapeutic efficacy. Finally, we address the principal translational challenges that must be resolved for broader clinical implementation, including neurotoxicity, manufacturing scalability and the development of predictive preclinical models.Collectively, these multidisciplinary advances provide a roadmap for optimizing CAR-T cell therapy in glioblastoma and accelerating its translation toward durable clinical benefit.