Age-Related Survival Disparities in Advanced Renal Carcinoma in the Immune Checkpoint Inhibitor Era using the SEER Database and Meta-analysis

Immunosenescence, the gradual deterioration of the immune system with age, reduces the efficacy of immune checkpoint inhibitors (ICI) in cancer management. Although ICI offer promising survival benefits for advanced renal cell carcinoma (aRCC), their effectiveness across different age groups remains poorly understood. This study aimed to evaluate age-related survival outcomes in aRCC patients receiving ICI using integrated cohorts. Using data from the Surveillance, Epidemiology, and End Results (SEER) program (2004-2021), we identified patients with aRCC across the pre-ICI and ICI eras and stratified them into younger (<65 years) and older (≥65 years) groups. Survival analyses, including Kaplan-Meier curves and multivariate Cox regression models, were performed to assess overall survival (OS). Key prognostic factors, such as tumor grade, surgical intervention, and metastatic status, were analyzed using nomograms and receiver operating characteristic (ROC) curves for predictive accuracy. A systematic search of PubMed, Web of Science, and Scopus also identified ten randomized controlled trials (RCTs) that met the meta-analysis criteria. Odds ratios (ORs) were calculated to evaluate age-stratified survival outcomes. Finally, laboratory-based immunohistochemistry (IHC) analysis of TNFSF15, an immune-related biomarker, was performed to explore molecular age-related differences in a hospital cohort. The SEER cohort included 21,904 patients (11,814 in the pre-ICI era and 10,090 in the ICI era). Age showed no significant impact on survival in the pre-ICI era (HR 1.050; 95% CI 0.97-1.32; p=0.203), while younger patients demonstrated superior outcomes in the ICI era (median OS, 16 vs. 13 months; HR, 1.37; 95% CI 1.24-1.51; p = 0.0001). Meta-analysis of 8,434 patients (4,207 ICI group, 4,227 control group) revealed significantly improved survival in younger patients receiving ICI (pooled OR 0.76; 95% CI 0.64-0.89; p<0.0001), whereas the non-ICI cohort showed no significant age-dependent effects (pooled OR 0.93; 95% CI 0.79-1.09; p = 0.37).When comparing ICI versus control treatments, younger patients derived greater benefit (HR 0.69 [0.62, 0.77]) than older patients (HR 0.84 [0.74, 0.96]) p<0.0001). TNFSF15 expression demonstrated a significant negative correlation with age (Spearman correlation = - 0.6, p = 0.0001), with significantly higher expression in patients aged <65 years to those ≥65 years (p=0.0001). This comprehensive analysis demonstrates the superior efficacy of ICI in younger aRCC patients across multiple cohorts, supporting the development of age-stratified therapeutic approaches. Age-dependent expression of TNFSF15 suggests potential molecular mechanisms underlying differential treatment responses.