Recurrent Limitations of CAR-T Therapy in Gliomas: Evidence from Preclinical and Phase I Clinical Studies

In recent years, the development of new immunotherapy strategies has been a significant breakthrough in cancer treatment. Among these, engineered T cell therapy with chimeric antigen receptors (CAR-T) has produced notable clinical results, especially in hematological malignancies. This success has sparked growing interest in extending the application of CAR-Ts to solid tumors, including gliomas. Gliomas-in particular, glioblastoma multiforme (GBM)-are among the most aggressive primary brain tumors, associated with a poor prognosis and a median survival of approximately one year after diagnosis. However, the translation of CAR-T therapy to gliomas presents significant challenges, related to factors such as tumor heterogeneity, presence of the blood-brain barrier (BBB), and a strongly immunosuppressive tumor environment. Despite this, in recent years, there has been an intensification of research efforts aimed at the identification of new antigenic targets and the development of preclinical models-both in vitro and in vivo-to evaluate the efficacy and safety of CAR-Ts in the treatment of gliomas. Despite promising results, currently available models still have essential limitations in faithfully reproducing the complexity of human gliomas. This review aims to offer an exhaustive overview of the most recent preclinical studies on CAR-T therapy in gliomas, with a focus on the identification of molecular targets, experimental strategies aimed at overcoming immunological barriers, and translational challenges that need to be addressed for future successful clinical implementation.