Sex-based heterogeneity in response to first-line immunotherapy plus chemotherapy in advanced esophageal squamous-cell carcinoma: a meta-analysis

Objective Amid acknowledged sex-based disparities in immune system response, the effect of patients’ sex on the efficacy of immune checkpoint inhibitors (ICIs) treatment remains inconsistent across cancers, and even inconclusive in esophageal squamous-cell carcinoma (ESCC). We conducted a systematic review and meta-analysis to assess the sex-based heterogeneity in response to first-line immunotherapy in advanced ESCC. Methods PubMed, Web of Science, Cochrane Library and Embase were searched from inception to December 1st, 2025 to retrieve randomized controlled trials (RCTs) investigating the efficacy of first-line immunotherapy plus chemotherapy versus chemotherapy alone for advanced ESCC. The studies reporting sex-stratified outcomes for overall survival (OS) with or without progression-free survival (PFS), were eligible for inclusion. Pooled hazard ratios (HRs) and 95%CI were calculated separately in men and women using a random-effects model, and the heterogeneity between the two estimates was assessed using an interaction test. Results Nine phase 3 RCTs, reporting on 4591 men (85.6%) and 773 women (14.4%), were included. An OS benefit of immunotherapy was found for both men (HR, 0.70; 95%CI, 0.65-0.75) and women (HR, 0.71; 95%CI, 0.58-0.87) in the overall population and in the PD-L1-positive subgroup (HR for men: 0.66, 95%CI, 0.55-0.80; HR for women: 0.48, 95%CI, 0.30-0.78). Similarly, the PFS benefit was found for both men (HR, 0.59; 95%CI, 0.54-0.63) and women (HR, 0.58; 95%CI, 0.46-0.74) in the overall population. Random-effects meta-analysis demonstrated no statistically significant study-level differences in response to immunotherapy between the sexes in the overall population (OS, I 2 = 14%; P = 0.94; PFS, I 2 = 18%; P = 0.95) as well as in the PD-L1-positive subgroup (PFS, I 2 = 0%; P = 0.24). Conclusion First-line immunotherapy plus chemotherapy can improve OS and PFS in advanced ESCC for both men and women. No evidence was found to support an association of sex with the efficacy of immunotherapy plus chemotherapy.