Engineering a Reversible Plant Hormone–Inducible ON-Switch Boosts Safety and Potency of CAR-T Cell Immunotherapy

The ability to externally regulate chimeric antigen receptor (CAR) activity via small molecules offers a promising strategy to enhance the safety and precision of adoptive T cell therapies. We present a novel inducible ON-switch CAR design that leverages plant hormone signaling components to achieve controllable T cell activation. Specifically, we engineered a receptor system that integrated the plant auxin receptor IAA7 and its co-receptor AFB1, enabling ligand-dependent interactions in response to the plant hormone auxin. Our results demonstrated that this auxin-inducible CAR (auxCAR) mediated rapid, reversible, and dose-dependent T cell activation, leading to potent cytotoxicity against Raji B-cell lymphoma in vitro and in vivo. Notably, auxCAR-T cells maintained a favorable memory T cell phenotype and exhibited reduced exhaustion markers compared with conventional CAR-T cells, translating into improved therapeutic efficacy. This plant hormone-based control system offers a versatile and orthogonal approach for precise modulation of CAR activity, with significant implications for the development of safer, more adaptable immunotherapies.