In this investigator-initiated, prospective, exploratory study, biomarkers predictive of clinical outcomes of first-line immune checkpoint inhibitor (ICI, nivolumab or pembrolizumab) plus XELOX(oxaliplatin and capecitabine) were identified in human epidermal growth factor receptor 2 (HER2)-negative patients with metastatic esophagogastric signet ring cell carcinoma. The findings showed an objective response rate (ORR) of 51.5% and a disease control rate of 86.8%, the median progression-free survival (PFS) for the entire cohort was 6.63 months. PD-L1 expression level in tumor tissues could not identify a high PD-L1 group that significantly benefited from ICI plus XELOX in terms of the ORR and PFS. By contrast, the patients expressing low exosomal PD-L1 or lactate in peripheral blood plasma before treatment initiation demonstrated a significantly increased ORR and prolonged PFS compared to that with high exosomal PD-L1 or lactate, patients with combining predictor of exosomal PD-L1 and lactate lower than - 0.249 was associated with a better ORR (82.1% vs. 30.0%, P <
0.001) and a longer median PFS (13.83 vs. 5.50 months, P <
0.001) compared to those with combining predictor ≥-0.249. The results also revealed that exosomal PD-L1 levels in peripheral blood plasma before the treatment were significantly correlated with the frequency of CD8