Mechanobiology of CAR-T cell therapy: regulatory mechanisms and strategies for enhanced antitumor immunity.

Chimeric antigen receptor (CAR) T cell therapy is a next generation precision immunotherapy that engineers a patient's own T cells to express synthetic CARs, thereby augmenting tumour cell recognition and cytotoxic activity. Despite transformative clinical success in haematologic cancers, nearly half of treated patients relapse or fail to respond, and the translation of CAR-T therapy to solid tumours remains substantially more challenging. Increasing evidence shows that biomechanical forces, including stretch, compression, shear stress, and extracellular matrix (ECM) stiffness, shape immune activation, trafficking, and effector function through mechanotransduction pathways, ultimately modulating immune responses and disease evolution. Biomechanical cues critically influence CAR-T function, governing target recognition, activation dynamics, and cytotoxic engagement. Furthermore, the mechanical landscape of the tumour microenvironment shapes T cell infiltration, persistence, and exhaustion, thereby constraining CAR-T efficacy. These insights have fueled growing interest in biomechanically informed strategies to optimize CAR-T therapies. Here, we review the biomechanical principles governing CAR-T antitumour responses and highlight how ECM rigidity, shear forces, and other mechanical cues shape CAR-T performance. Biomechanics informed strategies that enhance CAR-T cell antitumour immunity offer a novel conceptual framework for advancing precision cancer immunotherapy. Elucidating how CAR-T cells sense and adapt to the mechanical tumour microenvironment will guide the design of next generation products and accelerate their translation into solid tumour indications.