Chimeric antigen receptor (CAR)-T-based therapeutics are a breakthrough in cancer treatment; however, they are hampered by constitutive activation, which leads to worrisome side effects. Engineering CAR-T cells to be as tightly controllable as possible remains a topic of ongoing investigation. Here, we report a photoswitchable approach that uses a mediator for the at-will regulation of CAR-T cells. This mediator carries dual folate and fluorescein isothiocyanate moieties tethered by an ortho-nitrobenzyl ester photocleavable linker. CAR-T cells were shown to be highly cytotoxic to targeted cells only in the presence of the mediator and acted in a dose-dependent manner. The toxicity of CAR-T cells can be rapidly terminated by cleavage of the mediator, and the effects of CAR-T cells can be activated again by resupplementation with the mediator without compromising tumor therapy. The approach described here provides a direction for enhancing the controllability of CAR-T cells and can likely be applied in other immunotherapies.

基于嵌合抗原受体 (CAR)-T 的疗法是癌症治疗的突破；然而，它们受到组成性激活的阻碍，这会导致令人担忧的副作用。将 CAR-T 细胞设计为尽可能严格可控仍然是正在进行的研究课题。在这里，我们报告了一种光开关方法，该方法使用介质随意调节 CAR-T 细胞。这种介质带有双叶酸和异硫氰酸荧光素部分，由邻硝基苄酯光可裂解接头连接。CAR-T 细胞仅在介质存在时才对靶细胞具有高度细胞毒性，并且以剂量依赖性方式起作用。CAR-T 细胞的毒性可以通过介质的裂解迅速终止，CAR-T 细胞的作用可以通过补充介质再次激活，而不会影响肿瘤治疗。这里描述的方法为增强 CAR-T 细胞的可控性提供了一个方向，可能会应用于其他免疫疗法。