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 Mn²⁺ 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 (Mn²⁺) in NK cell activation. Mn²⁺ 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, Mn²⁺ 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, Mn²⁺ provides a promising option for NK cell-based immunotherapy of cancers.