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NK cell trafficking and migration into solid tumors is often poor. Altered NK cell metabolism in the tumor microenvironment has been correlated with tumor invasiveness, metastasis and cellular dysfunction. Tumor-induced stresses correlate to limited numbers of functional NK cells in solid tumors and, consequently, limited survival. Metabolic impairment of NK cells in cancer is still not fully understood, but the involvement of inhibitory checkpoints—both tumor-associated as well as NK-specific—plays a significant role in driving these responses. The metabolic reprogramming events that NK cells undergo in the tumor microenvironment are linked to their ability to support energy metabolism in scenarios of impaired glycolytic fueling and low oxygen. The contributions of inhibitory checkpoints to these events are not entirely known, but are emerging as increasingly significant to the restoration of NK cell function. Here, we discuss our understanding of the role of inhibitory receptors and checkpoints in the metabolic dysfunction of NK cells in solid tumors, as a critical key to the development of new immunotherapies

Immunometabolic Responses of Natural Killer Cells to Inhibitory Tumor Microenvironment Checkpoints