Repurposing a Small Molecule Plant Hormone as a Tunable ON-Switch for CAR-T Cell Immunotherapy.

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.