Abstract: Globally, there are pronounced sex disparities in cancer incidence and mortality, with males generally exhibiting higher incidence and mortality rates for non-reproductive cancers than females. Epidemiological studies indicate that among patients receiving immune checkpoint inhibitors (ICIs), males derive a greater overall survival benefit, whereas females tend to have higher response rates to combined immunotherapy. This review systematically elucidates the sex differences in non-reproductive cancers, encompassing the bidirectional regulation by sex hormones, the driving mechanisms of sex chromosome abnormalities, and the crosstalk between the tumor microenvironment and the gut microbiota. It highlights the necessity of integrating single-cell multi-omics technologies to dissect the interaction network among sex hormones, immunity, and metabolism. Furthermore, it advocates the development of sex-stratified immunotherapeutic strategies tailored to different hormonal statuses, tumor microenvironments, and microbial metabolites, thereby advancing precision immuno-oncology.