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
Affiliations
Lu Lu
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
Chao Yang
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
Xingyue Zhou
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
Lingling Wu
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xiaochuan Hong
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Wenwen Li
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xinran Wang
Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Yuanqin Yang
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Dongqing Cao
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Ao Zhang
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
Wen Di
Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Liufu Deng
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Corresponding author
Summary: 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.
