Metabolic Regulation of Natural Killer Cells

Abstract

Natural Killer cells, known as NK cells act crucially in protection of anti-tumor and anti-virus activities as innate lymphocytes. Due to its unique characteristics such as recognizing and attacking stressed cells independently, and bridge connection function between innate immunity and adaptive immunity, it possesses profound potential and prospect in immunotherapy. However, due to resistance existing in combination of therapies and undeclared metabolism pathways, its application in clinical trials has been underestimated. Metabolic configurations are adopted to support functions, which is dynamic when immune cells experience the procedure of metabolic reprogramming in responses. In order to support anti-tumor functions, NK cells up regulate both glycolysis and OXPHOS, leading to the alternative of energy metabolism structure and ATP relief upon activation with pro-inflammatory cytokines. After activation, what exactly determines phenotypes and destiny of NK cells is also being considered as the classification standard of receptors distribution is found both vague and not universally applicable. Additionally, author focus on metabolic factors in solid cancer treating, which are highly relative to tumor microenvironment (TME). TME provides many molecules for the prevention of potential effector function of normal cells (especially immune cells) and protection of tumor. For example, substances such as TGF-β are capable to not only downregulate NK cell cytotoxicity and cytokine secretion but also reduce the extent of metabolism and proliferation, and also induce effector NK cells to increase the production of ILC1-like characteristics. This review will discuss NK cells’ metabolic foundation to realize NK cell effector functions and analyze the relationship between phenotypes, NK cell fates and metabolism. Also, basing on impaired functions, immune suppression and resistance of joint therapies, the author will discuss different pathways and possible treating targets and therapies in order to boost cancer treatment progress such as adoptive NK cell therapy, bio- or tri- engager therapy and CAR-NK therapy.