Sex differences in immunotherapy plus chemotherapy: A systematic review and meta-analysis.

[BACKGROUND] Sex-based differences in immune response and cancer biology may influence treatment outcomes with immunotherapy combinations. Comprehensive evidence regarding whether biological sex affects the efficacy of immune checkpoint inhibitor plus chemotherapy regimens remains incomplete.

[METHODS] Following PRISMA guidelines, we systematically searched five databases through May 2025 for randomized controlled trials comparing immune checkpoint inhibitors plus chemotherapy versus chemotherapy alone in any cancer type. We performed a comprehensive meta-analysis with sex-stratified survival data, subgroup analyses across cancer types and treatment regimens, meta-regression, interaction testing with false discovery rate correction, and publication bias assessment.

[RESULTS] Seventy-nine trials enrolling 50,046 patients (30,503 males, 19,543 females) met inclusion criteria. Combination therapy significantly improved survival in both sexes: overall survival hazard ratios were 0.76 (95 % CI 0.73-0.78) in males and 0.78 (95 % CI 0.75-0.81) in females, representing 24 % and 22 % mortality reductions, respectively. Progression-free survival improved by 39 % in males (HR 0.61, 95 % CI 0.57-0.64) and 34 % in females (HR 0.66, 95 % CI 0.62-0.70). Overlapping confidence intervals and formal interaction testing revealed no statistically significant sex-based differences across cancer types, immunotherapy agents, histological subtypes, or chemotherapy backbones.

[CONCLUSIONS] Immune checkpoint inhibitors with chemotherapy provide significant and equivalent survival benefits for both male and female patients across cancer types. Treatment decisions should therefore be guided by tumor characteristics, not patient sex. These results support equitable treatment access and highlight the necessity for continued sex-stratified data reporting in clinical trials.