Clinical Outcomes and Tumor Immune Microenvironment in Epstein–Barr Virus-Positive Gastroesophageal Adenocarcinoma Treated with Immune Checkpoint Inhibitors

Epstein–Barr virus-positive gastroesophageal adenocarcinoma (EBV-GEA) is a distinct molecular subtype characterized by recurrent genomic and epigenetic alterations, frequent PD-L1/PD-L2 upregulation, and an immune-enriched tumor microenvironment. These features provide a strong biological rationale for immune checkpoint inhibition (ICI); however, clinical evidence remains limited, and EBV positivity is not currently established as an independent predictive biomarker for immunotherapy. We retrospectively identified consecutive patients with locally advanced or metastatic EBV-GEA treated with ICI-based regimens at a single tertiary cancer center between January 2016 and August 2025. EBV positivity was confirmed by Epstein–Barr virus-encoded RNA in situ hybridization. Clinical, pathological, treatment, and molecular data were collected. Treatment outcomes included best overall response, objective response rate (ORR), disease control rate (DCR), progression-free survival and disease-free survival when curative-intent surgery was performed. In patients with adequate tumor tissue, the tumor immune microenvironment was exploratorily characterized by immunohistochemical quantification of CD3+ and CD8+ T-cell densities. Eight patients with EBV-GEA were included. The ORR was 62.5% and the DCR was 75%. No consistent relationship between clinical outcome and HER2, PD-L1, Claudin 18.2 or mismatch repair status was observed. Tumor immune microenvironment assessment was feasible in five patients. Notably, the three patients with the highest CD3+ T-cell densities (>2000 cells/mm2, post hoc threshold) experienced the most favorable clinical outcomes, including two radiological partial responses followed by pathologic complete response and one prolonged partial response. In contrast, CD8+ T-cell density showed greater interpatient variability. ICI-based therapy demonstrated clinically meaningful activity in this small retrospective cohort of EBV-GEA, but benefit was not universal, highlighting substantial clinical and biological heterogeneity within this molecular subtype.