BackgroundThe impact of age on the efficacy and safety of immunotherapy remains controversial. The previous studies simply classified patients into younger and older groups, which might not reflect the real impact of young age on immunotherapy efficacy. The current study aimed to explore the efficacy and safety of immune checkpoint inhibitor (ICI) combined therapy in young (aged 18–44 years), middle-aged (aged 45–65 years), and old (aged >65 years) patients with metastatic gastrointestinal cancers (GICs), and further determine the role of immunotherapy in young patients.MethodsPatients with metastatic GIC including esophageal cancer (EC), gastric cancer (GC), hepatocellular cancer (HCC), and biliary tract cancer (BTC) who received ICI combination therapy were enrolled, divided into young (aged 18–44 years), middle-aged (aged 45–65 years), and old (aged >65 years) groups. The clinical characteristics, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared among three groups.ResultsA total of 254 patients were finally included, with 18, 139, and 97 cases in the young (aged 18–44 years), middle-aged (aged 45–65 years), and old (aged >65 years) groups, respectively. Compared to middle-aged and old patients, young patients had lower DCR (allp< 0.05) and also had inferior PFS (p< 0.001) and OS (p =0.017). The multivariate analyses showed that young age was an independent prognostic factor for PFS [hazard ratio (HR) 3.474, 95% confidence interval (CI) 1.962–6.150,p< 0.001] and OS (HR 2.740, 95% CI 1.348–5.570,p= 0.005). Subsequent safety analyses referring to irAEs demonstrated no significant differences for distribution frequency among each age group (allp> 0.05), whereas patients with irAEs displayed better DCR (p= 0.035) and PFS (p= 0.037).ConclusionYounger GIC patients (aged 18–44 years) showed poor efficacy for ICI combined therapy, and irAEs could be used as a clinical biomarker to predict ICI efficacy in metastatic GIC patients.