Deciphering the immunometabolic axis: a mendelian randomization study of a causal cascade network from immune cell phenotypes to metabolites in esophageal cancer.

Background: The causal relationship between immune cell phenotypes and esophageal cancer (EC) has not yet been fully elucidated. Further, the potential mediating role of metabolites in the relationship between immune cell phenotypes and EC remains largely unexplored. This study investigated the genetic mechanisms underlying the effects of immune cells on EC, and examined the mediating effects of metabolites. Methods: This study adopted a bidirectional two-sample Mendelian randomization (MR) approach to assess the causal relationship between immune cell phenotypes and EC. A reverse MR analysis was performed to eliminate potential reverse causation bias. Additionally, a two-step MR analysis and multivariable Mendelian randomization (MVMR) analysis were conducted to investigate potential metabolite mediators between immune cells and EC. Results: First, the bidirectional two-sample univariable MR analysis revealed statistically significant causal associations between 22 immune cell phenotypes and EC. A subsequent MRMR analysis was conducted to evaluate the independent causal effects of these phenotypes on EC, and revealed persistent significant correlations for three specific subtypes: CD38+ CD20- B cells, CD33+ CD14+ monocytes, and CD45+ CD33+ HLA-DR+ CD14dim cells. Finally, MVMR combined with a mediation analysis revealed that the aspartate to citrate ratio mediated 10.6% of the total effect between the CD33+CD14+ monocytes and EC. Conclusions: This study provides genetic evidence supporting the causal roles of specific immune cell phenotypes, particularly CD38+CD20- B cells, CD33+CD14+ monocytes, and CD45⁺CD33⁺HLA-DR+CD14dim myeloid cells, in promoting EC risk. Furthermore, we identified the aspartate to citrate ratio as a significant metabolic mediator in the pathway linking monocyte activity to esophageal carcinogenesis. These findings unveil a novel immunometabolic axis and highlight potential therapeutic targets for intervening in EC development.