Bladder cancer incidence shows an enigmatic male bias, as it is the 4th most common cancer in men but only the 12th most common cancer in women in Canada. The bias cannot be fully accounted for by lifestyle factors such as smoking, suggesting that it is likely a consequence of more fundamental biological differences between two sexes. To this end, we analyzed human primary bladder cancers and discovered that immune pathways are more enriched in women than in men, which hinted that sex bias may be driven by sex-specific differences in immune function. To address this possibility, we utilized the preclinical murine bladder cancer models that recapitulate the male bias seen in human bladder cancer. Remarkably, we observed that hormonally mediated differences in T cell immunity are responsible for sexual dimorphism in tumor growth. Our Research Proposal seeks to determine exact mechanisms by which sex hormones regulate T cell immunity. Male-based studies predominate in immunology research despite clear evidence that sex discrepancy exists in the outcome from many infectious and autoimmune diseases, vaccines and malignancies. Erroneous assumption that such results can be generalized to both sexes not only damages the scientific rigor and reproducibility but is also a major barrier to the long-term goal of personalizing treatments for immune-related diseases. Specific study design in our Proposal, explicitly aiming to highlight the immune mechanisms underlying unique protection against bladder cancer in females, presents an innovative approach to identify novel therapeutic targets. Also, completion of proposed research will establish an important insight that anti-tumor immunity may be largely different between men and women, thereby emphasizing sex as a critical biological variable to consider in designing future pre-clinical/clinical immunotherapy studies.