The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called ‘light-inducible SMOC-like repeats’ (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice.

cGAS-STING 信号通路已成为免疫疗法开发的一个有前景的靶标。在这里，我们引入了一种光敏光遗传学装置，用于控制 cGAS/STING 信号传导，以有条件地调节先天免疫，称为“光诱导 SMOC 样重复序列”(LiSmore)。我们证明光激活的 LiSmore 能够以高时空精度促进树突状细胞 (DC) 成熟和抗原呈递。这种非侵入性方法使细胞毒性 T 淋巴细胞光敏化，与肿瘤抗原结合，从而产生持续的抗肿瘤免疫反应。当与免疫检查点阻断剂 (ICB) 联合使用时，LiSmore 可以提高免疫抑制性肺癌模型的抗肿瘤功效，而该模型对传统 ICB 治疗没有反应。此外，LiSmore 通过有效抑制双侧黑色素瘤小鼠模型远端部位的肿瘤生长，表现出远隔效应。总的来说，我们的研究结果确立了 STING 信号通路的靶向光遗传学激活用于小鼠远程免疫调节的潜力。