Abstract

Background and Objectives: Metabolites, as key mediators of nutrition–immune interactions, have attracted increasing interest in cancer research. However, the causal relationships between immune cells, plasma metabolites, and esophageal cancer, and their potential for guiding nutritional interventions remain unclear. Methods and Study Design: We conducted a two-sample Mendelian randomization analysis using the inverse-variance weighted method to evaluate the causal effects of immune cells and plasma metabolites on esophageal cancer. We explored potential intermediary pathways by investigating associations between immune cell traits and plasma metabolites relevant to esophageal cancer risk. To test the robustness of our findings, we also carried out sensitivity analyses. Results: We identified 19 immune cell phenotypes associated with esophageal cancer risk (8 protective, 11 risk factors). In addition, 22 plasma metabolites (including 5 ratios) were protective, while 26 metabolites (including 8 ratios) increased risk, highlighting potential targets for nutritional interventions. Our analysis identified four plasma metabolites that were associated with specific immune cell traits relevant to esophageal cancer risk. Sensitivity analyses confirmed the robustness of the findings, with no significant heterogeneity or pleiotropy observed. Conclusions: This study provides genetic evidence for potential causal associations among immune cells, plasma metabolites, and esophageal cancer, and identifies observed associations between immune cell traits and plasma metabolites. These findings provide a foundation for precision nutrition and support dietary modification as a promising strategy for prevention and adjunctive therapy.

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