Exploring Risk Factors and Sex Differences in Colorectal Cancer: Insights from Current Evidence

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. A consistent and epidemiologically well-documented feature of CRC is its sexual dimorphism: age-standardized incidence rates are 33-45% higher in men than in women, and mortality rates differ by 43-50%. Beyond epidemiology, biological sex influences tumor location, molecular subtype, and clinical outcome. Women more frequently develop right-sided, microsatellite-unstable tumors driven by the CpG island methylator phenotype pathway, whereas men predominantly present with left-sided, chromosomally unstable tumors harboring APC, KRAS, and TP53 mutations. Sex steroid hormones play a central modulatory role: estrogens, primarily via estrogen receptor β (ERβ), exert tumor-suppressive effects on colonic epithelium, whereas androgens promote pro-inflammatory and pro-tumorigenic signaling through androgen receptor (AR)-dependent pathways. The gut microbiome displays sex-specific compositional profiles ('microgenderome') and contributes to sex-specific CRC susceptibility through bidirectional interactions with sex hormones, shaping distinct immunological and metabolic microenvironments. Finally, sex influences the pharmacokinetics of fluoropyrimidines, the toxicity of targeted agents, and the response to immune checkpoint inhibitors. This review summarizes current evidence on sex-related differences in CRC epidemiology, molecular pathology, hormonal regulation, gut microbiota composition, and treatment outcomes, highlighting the need to systematically incorporate sex as a biological variable in CRC research and clinical practice.