Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy

Abstract Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.