Natural killer cell infiltration elicits gender‐dependent dichotomous clinical outcomes in urothelial carcinoma

Abstract Background Sex differences are a hallmark of urothelial carcinoma (UC), and profoundly influence disease progression and therapeutic outcomes. As critical effector immune cells with intrinsic sexual dimorphism, the contributions of natural killer (NK) cells to this clinical discrepancy remain incompletely understood. Methods In this multicohort retrospective study of 885 patients with UC (671 males; 214 females), individuals were stratified into NK high and NK low subgroups on the basis of immunohistochemical or transcriptomic evaluation. The association of NK cells with clinical outcomes and the tumor immune microenvironment (TME) was systematically assessed across sexes. Single‐cell RNA sequencing and flow cytometry were deployed to decipher the functional state of NK cells. Results Although NK cell infiltration levels were comparable between sexes, their clinical impact was markedly divergent: high NK infiltration conferred a significant survival advantage and superior response to both chemotherapy and immunotherapy exclusively in male patients. Further immune profiling revealed that NK high male patients exhibited a coordinated antitumor microenvironment, characterized by immunotype A features, tertiary lymphoid structure formation, and abundant infiltration of dendritic cells and effector T cells. Mechanistically, male‐derived NK cells maintained robust cytotoxic and inflammatory programs, whereas female‐derived NK cells were polarized toward a stressed, dysfunctional state with decidual‐like characteristics. Conclusions Altogether, this study establishes NK cells as pivotal mediators of sex differences in UC. The stark contrast in NK cell phenotypes underscores a fundamental sexual dimorphism within the TME, which highlights the urgent need for sex‐tailored immunotherapy strategies.