Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function

BACKGROUND: Natural killer (NK) cells are responsible for monitoring and eliminating malignant or virus-infected cells. To become activated, NK cells must upregulate oxidative phosphorylation and glycolysis to meet the high energetic demands associated with cytotoxic and effector functions. While glutamine can also fuel the tricarboxylic acid cycle through its conversion to alpha-ketoglutarate, the precise role of this pathway in NK-cell cytotoxic activity is unclear. RESULTS: To investigate NK-cell dependency on glutamine, we selectively inhibited kidney-type glutaminase to prevent glutamine metabolism. We analysed the metabolism and cytotoxicity of expanded primary NK cells, treated or not with glutaminase inhibitor. Glutaminase inhibition significantly reduced oxidative phosphorylation and led to a significant decrease in NK cell cytotoxic function. Furthermore, glutaminase inhibition reduced protein synthesis in activated NK cells. Meanwhile, supplementation with alpha-ketoglutarate rescued both the metabolic and cytotoxic capacities of primary expanded NK cells. CONCLUSIONS: Our findings highlight the importance of glutaminase activity in supporting NK cell respiratory metabolism and cytotoxic function, and the need for caution when combining glutaminase inhibitors with NK cell-based therapies.