Te-Ding Chang,1,2 Yu-Jie Chen,1,2 Jia-Liu Luo,1,2 Cong Zhang,1,2 Shun-Yao Chen,1,2 Zhi-Qiang Lin,1,2 Pei-Dong Zhang,1,2 You-Xie Shen,1,2 Ting-Xuan Tang,3 Hui Li,1,2 Li-Ming Dong,1,2 Zhao-Hui Tang,1,2 Deng Chen,1,2 Yu-Man Wang4,5 

1Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 5Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

Correspondence: Deng Chen, Email chendeng@tjh.tjmu.edu.cn; Yu-Man Wang, Email wangyuman0927@tjh.tjmu.edu.cn

Abstract: As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.

Keywords: NK cells, hypoxia, immunotherapy, innate immunity, metabolism