UTY coordinates with UTX to repress NK cell development and maturation in males

Natural killer (NK) cells are pivotal innate lymphoid cells in anti-tumor immunity. However, the contribution of the Y chromosome-encoded epigenetic regulator UTY (also known as KDM6C) to male NK cell development and effector function remains poorly characterized. Here, we demonstrated that conditional deletion of UTY in NK cells (Ncr1-iCre) in male mice led to a statistically significant but modest increase in total NK cell numbers (P < 0.05) and an elevated frequency of terminally differentiated CD27-CD11b+ subset in the spleen. Strikingly, UTY-deficient NK cells displayed impaired cytotoxic function, with significantly reduced granzyme B expression (P < 0.05) and attenuated control of B16F10 melanoma pulmonary metastases in vivo (P < 0.05). Importantly, combined UTX-UTY deficiency exacerbated these phenotypes, causing further increase in NK cell abundance, and decline in CD27+CD11b+ subset proportions and granzyme B expression level compared with UTX single knockout in male mice. RNA-sequencing combined with qRT-PCR validation uncovered significant downregulation of key genes involved in NK cell maturation (Cd27), cytotoxicity (Gzmb), survival (Bax, Casp3) and transcriptional regulation (Socs3, Tcf7, Fos) in UTY-deficient NK cells. Notably, dual UTX-UTY depletion synergistically repressed Casp3 expression, potentially contributing to the altered NK cell abundance (P < 0.05). These findings establish UTY as a sex-specific epigenetic modulator that restricts NK cell maturation while promoting cytotoxic function. Our data further reveal a cooperative role for UTY and UTX in orchestrating NK cell development via transcriptional regulation.