STING signaling promotes NK cell antitumor immunity and maintains a reservoir of TCF-1+ NK cells
Lu Lu, Chao Yang, Xingyue Zhou, Lingling Wu, Xiaochuan Hong, Wenwen Li, Xinran Wang, Yuanqin Yang, Dongqing Cao, Ao Zhang, Wen Di, Liufu Deng
Abstract
Natural killer (NK) cells are cytotoxic innate lymphocytes that eradicate tumor cells. Inducing durable antitumor immune responses by NK cells represents a major priority of cancer immunotherapy. While cytosolic DNA sensing plays an essential role in initiating antitumor immunity, the role of NK cell-intrinsic STING signaling remains unclear. Here, we find that NK cell-intrinsic STING promotes antitumor responses and maintains a reservoir of TCF-1 + NK cells. In contrast, tumor cell-intrinsic cGAS and mtDNA are required for NK cell antitumor activity, indicating that tumor mtDNA recognition by cGAS partially triggers NK cell-intrinsic STING activation. Moreover, addition of cGAMP enables STING activation and type I interferon production in NK cells, thereby supporting the activation of NK cells in vitro . In humans, STING agonism promotes the expansion of TCF-1 + NK cells. This study provides insight into understanding how STING signaling drives NK cell antitumor immunity and the development of NK cell-based cancer immunotherapy.