BackgroundCurrently, immune checkpoint inhibitors (ICIs) have become a mainstay in treating advanced esophageal cancer (EC), yet the predictive significance of routinely collected clinicopathological characteristics for overall survival (OS) remains uncertain.MethodsWe searched EMBASE, MEDLINE, Cochrane Library, Web of Science, and ClinicalTrials.gov for phase III randomized controlled trials (RCTs). Eligible studies reported OS for the overall population and subgroups stratified by various clinicopathological features. Pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated.ResultsA total of 13 phase III RCTs involving 7696 advanced EC patients were included. Pooled analysis showed immunotherapy was associated with favorable outcomes (HR = 0.73; 95% CI, 0.69–0.77; P < 0.001). Although both PD-L1-positive and PD-L1-negative patients can benefit from ICIs, there was a robust PD-L1 expression-treatment interaction (PInteraction = 0.004). Esophageal squamous cell carcinoma (ESCC; HR = 0.73; 95% CI, 0.64–0.84; P = 0.001) patients, but not esophageal adenocarcinoma (EAC; HR = 0.92; 95% CI, 0.76–1.13; P = 0.44) patients, experienced survival benefits from immunotherapy. Asian patients derived greater benefits (HR = 0.68; 95% CI, 0.62–0.75) than non-Asian patients (HR = 0.81; 95% CI, 0.77–0.91; PInteraction = 0.03). Notably, ICIs conferred consistent OS benefits across most clinicopathological subgroups categorized based on sex, age, body weight, smoking, ECOG performance status, disease stage, number of metastatic organs, and liver/lung metastasis.ConclusionImmunotherapy significantly improves outcomes in advanced esophageal cancer. However, for EAC patients, clinicians must thoughtfully evaluate the treatment effectiveness, safety, and patient preferences to provide personalized management. PD-L1 expression and race tend to be associated with better outcomes rather than acting as a standalone indicator for patient stratification. Other routinely evaluated clinicopathological features showed no significant modulating effect on immunotherapy efficacy.Systematic Review RegistrationIdentifier CRD420261348582.