Natural Killer (NK) cells are characterized by their potential to kill tumor cells by different means without previous sensitization and have, therefore, become a valuable tool in cancer immunotherapy. However, their efficacy against solid tumors is still poor and further studies are required to improve it. One of the major restrictions for NK cell activity is the immunosuppressive tumor microenvironment (TME). There, tumor and other immune cells create the appropriate conditions for tumor proliferation while, among others, preventing NK cell activation. Furthermore, NK cell metabolism is impaired in the TME, presumably due to nutrient and oxygen deprivation, and the higher concentration of tumor-derived metabolic end products, such as lactate. This metabolic restriction of NK cells limits their effector functions, and it could represent a potential target to focus on to improve the efficacy of NK cell-based therapies against solid tumors. In this review, we discuss the potential effect of TME into NK cell metabolism and its influence in NK cell effector functions.

A brief in vitro stimulation of natural killer (NK) cells with interleukin (IL)-12, IL-15, and IL-18 endow them a memory-like behavior, characterized by higher effector responses when they are restimulated after a resting period of time. These preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have several properties that make them a promising tool in cancer immunotherapy. In the present study, we have described the effect that different combinations of IL-12, IL-15, and IL-18 have on the generation of human CIML NK cells. Our data points to a major contribution of IL-15 to CIML NK cell-mediated cytotoxicity against target cells. However, the synergistic effect of the three cytokines grant them the best polyfunctional profile, that is, cells that simultaneously degranulate (CD107a) and produce multiple cytokines and chemokines such as interferon γ, tumor necrosis factor α, and C-C motif chemokine ligand 3. We have also analyzed the involvement of each cytokine and their combinations in the expression of homing receptors CXCR4 and CD62L, as well as the expression of CD25 and IL-2-induced proliferation. Furthermore, we have tested the effects of the Jak1/2 inhibitor ruxolitinib in the generation of CIML NK cells. We found that ruxolitinib-treated CIML NK cells expressed lower levels of CD25 than non-treated CIML NK cells, but exhibited similar proliferation in response to IL-2. In addition, we have also found that ruxolitinib-treated NK cells displayed reduced effector functions after the preactivation, which can be recovered after a 4 days expansion phase in the presence of low doses of IL-2. Altogether, our results describe the impact that each cytokine and the Jak1/2 pathway have in the phenotype, IL-2-induced proliferation, and effector functions of human CIML NK cells.

Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has been reported in renal cell carcinoma (RCC), the most frequent kidney cancer in adults, and their presence has been associated with patients’ survival. However, the role of NK cells in this disease is not yet fully understood. In this review, we summarize the biology of NK cells and the mechanisms through which they are able to recognize and kill tumor cells. Furthermore, we discuss the role that NK cells play in renal cell carcinoma, and review current strategies that are being used to boost and exploit their cytotoxic capabilities.

NK cells are lymphocytes with potent antitumor functions and, therefore, multiple NK cell-based cancer immunotherapies have been developed and are currently being tested. However, there is a necessity to find new means to improve these therapies, and immunometabolism represents an attractive target. NK cell effector functions are intricately linked to their metabolism, and modulating the latter could be the key to release their full potential. In this review, we have summarized how NK cell metabolism is regulated during some processes, such as maturation, viral infection and cytokine stimulation. Additionally, we provide an overview of how NK cell metabolism is affected by current therapeutic approaches aimed to promote NK cell expansion and/or to increase their effector functions. We have also recapitulated several strategies that could help alleviating the metabolic impairment that characterizes tumor-infiltrating NK cells, and thus increase or restore their effector functions. Furthermore, we have reviewed several therapeutic approaches targeting cancer metabolism that could synergize with NK cell-based cancer immunotherapies, and thus enhance their efficacy.