肿瘤细胞治疗研究
英文原题：Repurposing a Small Molecule Plant Hormone as a Tunable ON-Switch for CAR-T Cell Immunotherapy.
精确调控嵌合抗原受体（CAR）-T细胞活性对于最大化疗效和最小化毒性至关重要。
精确调控嵌合抗原受体（CAR）-T 细胞活性对于最大化疗效和最小化毒性至关重要。尽管开关控制的 CAR-T 具有巨大前景，但在实现精准激活、降低免疫原性和防止脱靶效应方面仍存在挑战。在此，我们提出一种新型可诱导 ON 开关 CAR 设计，其利用植物激素信号组分实现可控的 T 细胞激活。通过工程化改造一个将植物生长素受体 AFB1 与其共受体 IAA7 整合的受体系统，我们实现了由植物激素生长素触发的配体依赖性相互作用。该设计允许快速、可逆且剂量依赖性的 T 细胞激活，从而在体外和体内对 B 细胞淋巴瘤产生强效细胞毒性。值得注意的是，由合成生长素类似物控制的 auxCAR-T 细胞在治疗期间维持良好的记忆表型，并表现出功能性耗竭减少，从而提高治疗疗效。我们基于植物激素的正交系统克服了现有开关系统的关键局限，并推进了精准 CAR-T 疗法的发展。
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.
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