New Frontier in Cancer Immunotherapy: Sexual Dimorphism of Immune Response

Sexual dimorphism influences immune responses, cancer progression, and therapeutic outcomes, yet its metabolic underpinnings remain underexplored. Metabolomics enables the comprehensive profiling of biochemical pathways that shape sex-based differences in immune function and immunotherapy efficacy. Meta-analytic data indicate that men achieve a larger overall survival benefit from immune checkpoint inhibitors than women (pooled hazard ratio 0.72, 95% CI 0.65-0.79 vs. 0.86, 95% CI 0.79-0.93), while women may experience higher major pathologic response rates in neoadjuvant settings. At the biomarker level, elevated kynurenine-to-tryptophan ratios-reflecting indoleamine 2,3-dioxygenase activity-and distinct lipidomic signatures associate with reduced immunotherapy efficacy and may vary by sex. Sex-specific differences in microbiome-derived metabolites, including short-chain fatty acids, further modulate systemic immunity and treatment response. Ongoing clinical investigations combine hormone modulation with immune checkpoint blockade and increasingly integrate metabolomic profiling to identify predictors of benefit and toxicity. This review will synthesize meta-analytic and mechanistic evidence on sex differences in immunotherapy outcomes, highlight metabolomic biomarkers linked to response, and summarize ongoing clinical trials that incorporate metabolomics to guide sex-aware precision oncology. Understanding sex-specific metabolic pathways can refine patient stratification and optimize immunotherapeutic strategies.