Glutathione enhances antitumor activity of NK cells via modulation of mitochondrial metabolism in acute leukemia patients

Natural killer (NK) cell function is markedly impaired in acute leukemia patients, weakening their antitumor immune response; however, the specific mechanisms underlying these functional deficits remain incompletely understood. Here, we reveal the critical role of glutathione (GSH) metabolism in maintaining NK cell homeostasis and function. Compared with healthy individuals, NK cells from acute leukemia patients exhibit markedly reduced GSH levels. GSH depletion impairs NK cell cytotoxic activity, cytokine production, and proliferative capacity. Notably, supplementation with glutathione reduced ethyl ester (GSHEE) enhances the antileukemic activity of NK cells. Mechanistically, GSH supports optimal NK cell function by improving mitochondrial function and promoting oxidative phosphorylation (OXPHOS). In summary, this study identifies disrupted GSH metabolism as a driver of NK cell dysfunction in acute leukemia and suggests that GSH supplementation may enhance NK cell-mediated antileukemic effects, offering a potential new strategy for NK cell-based immunotherapy. Overall design: To explore the regulatory effect of BSO on HC-NK cell function, we isolated and purified NK cells from the peripheral blood of 3 healthy donors and treated them with BSO for 72 hours. To explore the effect of GSHEE on AL-NK cells, we isolated and purified NK cells from the peripheral blood of 4 acute leukemia patients and treated them with GSHEE for 12 hours.