Ultrasound controllable and antigen-independent killing via cis-activating CAR T cells.

Clinical efficacy of chimeric antigen receptor (CAR) T cell therapy is limited by tumor antigen escape and heterogeneity, leading to cancer relapse. To address this limitation, we developed a focused ultrasound (FUS) controllable and cis-activated CAR (FUS-CisCAR) platform, in which CAR T cells are engineered to express their own target antigen upon FUS stimulation. This self-supplied antigen triggers a "cis-activation" loop, initiating a localized bystander effect to eliminate nearby tumor cells, including those that lack the target antigen. We demonstrate that primary human FUS-CisCAR T cells effectively kill local antigen-negative tumor cells in both in vitro and in vivo models. The FUS-CisCAR platform offers a controllable strategy that has the potential to overcome relapse caused by tumor heterogeneity and antigen escape, thus enhancing the durability of CAR T cell therapy.