Abstract Men and women show striking yet unexplained discrepancies in incidence, clinical presentation, and therapeutic response across different types of infectious/autoimmune diseases and malignancies 1,2 . For instance, bladder cancer shows a 4-fold male-biased incidence that persists after adjustment for known risk factors 3,4 . Here, we utilize murine bladder cancer models to establish that male-biased tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex differences exist in early fate decisions by intratumoral CD8 + T cells following their activation. While female CD8 + T cells retain their effector function, male counterparts readily adopt a Tcf1 low Tim3 − progenitor state that becomes exhausted over tumor progression. Human cancers show an analogous male-biased frequency of exhausted CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell intrinsic androgen and type I interferon 5,6 signaling in Tcf1/ Tcf7 regulation and formation of the progenitor exhausted T cell subset. Consistent with female-biased interferon response 7 , testosterone-dependent stimulation of Tcf1/ Tcf7 and resistance to interferon occurs to a greater magnitude in male CD8 + T cells. Male-biased predisposition for CD8 + T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder tumors is less common in males and carries implications for therapeutic efficacy of immune checkpoint inhibitors 8,9 .

Distinct CD8+ T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome