Аннотация:The use of tumor-associated antigens to target solid tumors by chimeric antigen receptor (CAR) T cells remains limited by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Programmable CAR systems are being developed to achieve more sophisticated tumor recognition and enhance the controllability of CAR T cells. Here, we propose to harness the RNase toxin barnase as a targeting module that provides the cytotoxic effects itself or in combination with CAR T cells. Molecular switches based on the DARPin-barnase proteins and universal barstar-based CAR (BsCAR) were designed and validated in vitro and in vivo. We expect this strategy may be a promising approach for the generation of safe and efficient CAR T cell therapy against solid tumors.