Repurposing a Small Molecule Plant Hormone as a Tunable ON‐Switch for CAR‐T Cell Immunotherapy
Hongxiang Zeng, Lei Zheng, Rongkun Tao, Sirui Zheng, Yanke Zhong, Yongxia Niu, Peng Zhang, Xiang Ma, Chen Yang, Min Zhang, Fuyu Duan, Jing Yang, Xuan Wei, Xiang Zhou, Zhenbiao Yang, Zhaoxi Sun, Qizhou LianABSTRACT
Precise regulation of chimeric antigen receptor (CAR)‐T cell activity is essential to maximize efficacy and minimize toxicity. While switch‐controlled CAR‐T holds great promise, challenges remain in achieving accurate activation, reducing immunogenicity, and preventing off‐target effects. Here we present a novel inducible ON‐switch CAR design that leverages plant hormone signaling components to achieve controllable T cell activation. By engineering a receptor system integrating the plant auxin receptor AFB1 with its co‐receptor IAA7, we enable ligand‐dependent interactions triggered by the plant hormone auxins. This design allows rapid, reversible, and dose‐dependent T cell activation, resulting in potent cytotoxicity against B‐cell lymphoma in vitro and in vivo. Notably, auxCAR‐T cells controlled by synthetic auxin analogs maintain a favorable memory phenotype and exhibit reduced functional exhaustion during treatment, leading to improved therapeutic efficacy. Our plant hormone‐based orthogonal system overcomes key limitations of existing switch systems and advances the development of precision CAR‐T therapies.