Manganese boosts natural killer cell function via cGAS-STING mediated UTX expression.

Natural killer (NK) cells play a crucial role in both innate immunity and the activation of adaptive immunity. The activating effect of Mn on cyclic GMP-AMP(cGAS)-stimulator of interferon genes (STING signaling has been well known, but its effect on NK cells remains elusive. In this study, we identified the vital role of manganese (Mn) in NK cell activation. Mn directly boosts cytotoxicity of NK cells and promotes the cytokine secretion by NK cells, thereby activating CD8+ T cells and enhancing their antitumor activity. Furthermore, Mn can simultaneously activate NK-cell intrinsic cGAS and STING and consequently augment the expression of ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX to promote the responsiveness of NK cells. Our results contribute to a broader comprehension of how cGAS-STING regulates NK cells. As a potent agonist of cGAS-STING, Mn provides a promising option for NK cell-based immunotherapy of cancers.