Chimeric antigen receptor (CAR) T cells have transformed the treatment of hematological malignancies but remain largely ineffective against solid tumors, highlighting the need for innovative strategies to enhance their activity. While recent CAR designs have focused on optimizing biochemical signaling, the biomechanical aspects of T cell activation have been widely overlooked. Yet, T cells are also regulated by the biophysical properties of their targets. Upon engagement, they form an immune synapse (IS) and sense mechanical cues through mechanosensitive receptors, which directly shape their cytotoxic function. These forces depend on target compliance and stiffness, which vary during cancer progression and may act as a “mechanical immune checkpoint” that facilitates tumor immune evasion. We hypothesize that CAR-T cells respond differently to biophysical cues compared with TCR-activated T cells, as suggested by their non-classical IS, morphological changes, and incomplete cytoskeletal remodeling. This reduced mechanosensitivity likely contributes to their limited efficacy in solid tumors. Our project aims to enhance CAR-T performance by (i) mapping how target mechanics influence activation and identifying key mechanosensitive proteins, and (ii) engineering CARs with enhanced force sensing. By integrating biomechanics into the CAR-T engineering toolkit, we aim to open new avenues for overcoming the barriers that currently limit their effectiveness against solid tumors.

Paris postdoc seminar series