Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia

Natural killer (NK) cell function is markedly impaired in patients with acute leukemia, weakening their anti-tumor immune response. However, the mechanisms underlying NK cell dysfunction are not fully understood. Here, we reveal that NK cells from patients with acute leukemia (AL-NK) exhibit significantly reduced intracellular glutathione (GSH) levels, accompanied by disrupted redox homeostasis and increased levels of mitochondrial reactive oxygen species. Flow cytometry and transcriptomic analyses indicate that dysregulated GSH metabolism leads to mitochondrial dysfunction in NK cells, thereby impairing their antileukemic cytotoxicity and proliferative capacity. Notably, supplementation with glutathione reduced ethyl ester (GSHEE)-a GSH precursor-effectively restores GSH levels in AL-NK cells, enhancing mitochondrial activity, oxidative phosphorylation, ATP production, and NK cell-mediated cytotoxicity. Moreover, GSHEE treatment activates the mTOR signaling pathway in NK cells, further promoting their function and proliferation. Overall, our study identifies dysregulated GSH metabolism as a key driver of NK cell dysfunction in acute leukemia and suggests that GSH-based interventions may provide a promising strategy to enhance NK cell-mediated immunotherapies.