Abstract
Esophageal cancer (EC) remains a major global health burden, and emerging research highlights the potential influence of the gut microbiome on its pathogenesis. However, the causal relationship between specific microbial taxa and EC, as well as the immunological mechanisms mediating these effects, remains unclear. A 2-sample Mendelian randomization analysis was performed using data from 619 EC cases and 314,193 controls in the FinnGen R10 cohort, together with genome-wide association summary statistics of 412 gut microbiota taxa and 731 immune phenotypes obtained from the National Human Genome Research Institute-European Bioinformatics Institute Genome-Wide Association Studies Catalog. The analysis aimed to determine causal links between the gut microbiome and EC, and to explore immune cell-mediated pathways through mediation analysis. The results revealed a significant protective association between Streptococcus thermophilus and EC risk (odds ratio = 0.586, 95% confidence interval = 0.402-0.855, P = .006). Mediation analysis indicated that terminally differentiated CD4+ T cells partially mediated this relationship, accounting for approximately 6% of the total effect. This study identifies Streptococcus thermophilus as a potentially protective gut commensal that may reduce EC risk through immune modulation. The findings provide novel insights into microbiome-immune-cancer interactions and suggest possible preventive or therapeutic targets for EC.