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Repurposing a Small Molecule Plant Hormone as a Tunable ON-Switch for CAR-T Cell Immunotherapy
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DOI：10.1002/advs.77020.png)
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Abstract
En 中文
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.
Keywords:
auxin
cell biology
chimeric antigen receptor
cytotoxicity
hormone
immunogenicity
immunotherapy
plant hormone
small molecule
t cell
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