Biological basis of sex differences in cancer and characteristics of response to immunotherapy

Sex differences represent a core hallmark of cancer epidemiology and biology, manifesting in divergent incidence, progression, and therapeutic responses across genders. Globally, males exhibit higher overall cancer incidence and mortality, with marked predominance in lung, liver, bladder, and esophageal cancers, while breast cancer remains the most prevalent and lethal malignancy in females. These disparities arise from the interplay of extrinsic risk factors such as smoking, obesity, and chronic inflammation, and intrinsic biological determinants that drive sex-specific oncogenic pathways. Chromosomally, females benefit from X-chromosome dosage compensation and incomplete inactivation, enabling biallelic expression of tumor-suppressor genes that enhance tumor resistance by buffering against single-allele mutations. In contrast, males face elevated risks due to somatic Y-chromosome loss or transcriptional downregulation of Y-linked antitumor genes, which impairs antitumor immunity, remodels the tumor microenvironment, and promotes metastasis. Sex hormones exert multifaceted effects on oncogenic trajectories via hypothalamic-pituitary axis regulation. Estrogen acts through ERα/ERβ to enhance stem cell self-renewal and telomerase activity, with dysregulation increasing leukemia risk, while androgen maintains male hematopoietic stem cell homeostasis, and reduced secretion in elderly males elevates myeloid malignancy susceptibility. Sex hormones also reshape the tumor microenvironment: estrogen-ERα complexes accelerate breast cancer progression by recruiting stromal precursors, whereas androgen selectively drives angiogenesis in male endothelial cells. Metabolic dimorphisms further contribute to sex disparities: males display enhanced glycolysis and lactate production, with GLUT1 and MCT4 overexpression fueling tumor proliferation and immunosuppression, while females rely on adiponectin-mediated anti-inflammatory effects to mitigate cancer risk. Additionally, sex-specific gut microbiota profiles diverge, as males develop pro-inflammatory “obesity microbiomes” under high-fat diets, while female microbiota boost bile acid secretion to regulate lipid metabolism. Moreover, sex-specific DNA damage repair mechanisms exist—androgens upregulate DDR genes like ATM and BRCA1 in prostate cancer, while estrogen-ERα complexes boost double-strand break repair efficiency in breast cancer. Clinical and animal studies confirm that males have higher cancer risks after ionizing radiation exposure, due to weaker DNA damage repair capacity, as evidenced by male esophageal cancer cells’ heightened sensitivity to WEE1 inhibitors. These discrepancies, together with autosomal sex-biased gene regulation, further amplify gender-specific cancer vulnerabilities.Notably, sex differences profoundly impact immune checkpoint inhibitor (ICI) efficacy and safety. Males gain greater benefits from ICI monotherapy across most solid tumors, whereas females respond better to ICI-chemotherapy combinations, particularly in non-small cell lung cancer, with median overall survival reaching 18.6 monthsversus 14.3 monthsin males. Females also face a 49% higher risk of grade≥3 immune-related adverse events (irAEs), with distinct organ-specific toxicity profiles: females are more prone to pneumonitis, thyroid dysfunction and rash, while males exhibit higher incidence of life-threatening renal irAEs. Mechanistically, these outcomes stem from sex-biased immune polarization, with males favoring Th17 polarization and females skewing toward Th1 responses, differential PD-L1 expression and tumor mutation burden (TMB), and hormonal regulation of immune tolerance via molecules like AIRE.In conclusion, integrating sex as a biological variable is pivotal for precision oncology. Future research should prioritize sex-stratified clinical trials, explore hormone-ICI combination therapies such as androgen deprivation therapy (ADT) combined with PD-1 inhibitors, and identify sex-specific biomarkers to optimize treatment outcomes. Addressing these sex disparities will not only improve therapeutic efficacy but also reduce gender-related healthcare gaps in cancer management.