Chimeric antigen receptor (CAR) T cell-based immunotherapy, approved by the US Food and Drug Administration, has shown curative potential in patients with haematological malignancies. However, owing to the lack of control over the location and duration of the anti-tumour immune response, CAR T cell therapy still faces safety challenges arising from cytokine release syndrome and on-target, off-tumour toxicity. Herein, we present the design of light-switchable CAR (designated LiCAR) T cells that allow real-time phototunable activation of therapeutic T cells to precisely induce tumour cell killing. When coupled with imaging-guided, surgically removable upconversion nanoplates that have enhanced near-infrared-to-blue upconversion luminescence as miniature deep-tissue photon transducers, LiCAR T cells enable both spatial and temporal control over T cell-mediated anti-tumour therapeutic activity in vivo with greatly mitigated side effects. Our nano-optogenetic immunomodulation platform not only provides a unique approach to interrogate CAR-mediated anti-tumour immunity, but also sets the stage for developing precision medicine to deliver personalized anticancer therapy.

美国食品和药物管理局批准的基于嵌合抗原受体 (CAR) T 细胞的免疫疗法已在血液系统恶性肿瘤患者中显示出治疗潜力。然而，由于对抗肿瘤免疫反应的位置和持续时间缺乏控制，CAR-T细胞治疗仍面临细胞因子释放综合征和靶向、非肿瘤毒性等安全挑战。在此，我们展示了光可切换 CAR（指定为 LiCAR）T 细胞的设计，该细胞允许实时光可调激活治疗性 T 细胞以精确诱导肿瘤细胞杀伤。当与成像引导的、可手术移除的上转换纳米板结合使用时，该纳米板具有增强的近红外到蓝色上转换发光作为微型深层组织光子换能器，LiCAR T 细胞能够在体内对 T 细胞介导的抗肿瘤治疗活性进行空间和时间控制，并大大减轻副作用。我们的纳米光遗传学免疫调节平台不仅为研究 CAR 介导的抗肿瘤免疫提供了一种独特的方法，而且为开发精准医学以提供个性化的抗癌治疗奠定了基础。