Chimeric antigen receptor T-cell therapy for solid tumors: A review of the intricate mechanisms and potential strategies.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized cancer immunotherapy, achieving remarkable success in hematological malignancies. However, its clinical application to solid tumors is hindered by significant challenges, including tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), and physical barriers that limit effective T-cell infiltration. This review examines the intricate mechanisms of CAR-T therapy, with a focus on T-cell engineering, activation, and tumor targeting, highlighting the interplay between therapeutic design and tumor-specific complexities. The barriers unique to solid tumors, such as immune evasion mediated by suppressive cytokines and regulatory cells, tumor antigen escape, and the resilience of the extracellular matrix, are critically analyzed. Innovative strategies, including multi-antigen targeting constructs, logic-gated CARs for tumor-selective activation, and armored CAR-T cells equipped to counteract immunosuppressive signals, are evaluated for their potential to enhance therapeutic efficacy. Furthermore, the incorporation of matrix-degrading enzymes and immune checkpoint inhibitors is discussed as a means to overcome physical and immune-mediated resistance. Emerging targets such as B7-H3, Claudin 18.2, and MUC1, along with advancements in companion diagnostics, are reshaping the landscape of CAR-T therapy by enabling more precise patient selection and real-time therapeutic monitoring. This review synthesizes recent progress and persisting challenges, aiming to provide a comprehensive framework for advancing CAR-T therapy into a transformative modality for the treatment of solid tumors.