The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

SIMPLE SUMMARY: Natural killer cells are able to effectively eliminate tumor cells without previous sensitization, therefore the interest in their application in tumor immunotherapy has recently increased. However, tumor cells synergize with tumor-associated cells to create a specific immunosuppressive niche, which limits the activity of NK cells. In this review, we provide a detailed description of molecular mechanisms responsible for NK cells’ cytotoxic machinery. Moreover, we shortly characterize the tumor microenvironment and summarize how various metabolic factors within the tumor niche modulate antitumor capacity of NK cells. Moreover, we discuss the potential strategies and implications for the novel antitumor therapies augmenting NK cells functions. ABSTRACT: NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.