Molecular mechanisms and clinical impacts of sex differences in urologic cancers

Urological cancers exhibit significant sex differences in incidence, treatment response, and prognosis, with males generally showing higher morbidity and mortality. This review systematically summarizes the underlying molecular and clinical mechanisms of these disparities, focusing on sex hormones, chromosome biology, tumor immune microenvironment, and microbiota. Sex hormones modulate key tumor processes including proliferation, apoptosis, non-apoptotic cell death, and DNA repair. Genetic factors such as X chromosome inactivation escape genes and Y chromosome loss also contribute to sex-biased cancer susceptibility. Furthermore, sex-specific differences in the urinary system and gut microbiota influence local immunity and inflammation, thereby affecting tumor progression and therapeutic response. Lifestyle and environmental factors, including smoking, alcohol consumption, and occupational exposures, further exacerbate these disparities. Clinically, sex differences impact the efficacy of immunotherapy and targeted therapies, underscoring the need for sex-informed treatment strategies. Integrating sex as a biological variable in research, clinical practice, and public health policies is essential for advancing precision oncology in urologic cancers.