Genetic Evidence for Immune Cell-Lipid Mediation Pathways Linked to Esophageal Cancer and Associated Throat/Chest Pain Phenotypes

Purpose: Previous studies showed complex associations between immune cells and esophageal cancer (EC). EC-related pain is closely linked to immune dysregulation and abnormal lipid metabolism, but their synergistic regulatory mechanisms remain unclear. This study aimed to investigate causal relationships between immune cell traits and EC, explore plasma lipids’ mediating role, supplement genetic evidence for core immune factors-lipids-pain associations, and provide targets for EC’s combined “ Antineoplastic-analgesic” intervention. Methods: Genome-wide association study summary data of 731 immune cell traits, 179 lipid metabolites, 998 EC cases, and two pain-related datasets were compiled. Bidirectional MR analysis (with inverse variance weighting, MR-Egger, MR-RAPS, weighted median, weighted mode) was used to infer causal relationships, followed by sensitivity analyses for robustness and FDR correction (Benjamini-Hochberg method) to account for multiple testing. A two-step Mendelian randomization was applied to explore plasma lipids mediating role in the immune cell-EC risk link. Results: This study identified 24 immune cell phenotypes and 14 plasma lipids suggestive causal associations with EC risk. Mediation analysis revealed that HLA DR on CD33dim HLA DR+ CD11b+ affected EC risk via Phosphatidylcholine (18:0_22:6) levels, with a suppression ratio of − 82.15%, indicating an exploratory indirect effect that partially offsets the primary protection. Similarly, Phosphatidylcholine (O-18:1_20:4) exhibited a suggestive suppression effect (− 10.38%) on the association between SSC-A on CD8+ T cell and EC risk. Furthermore, CD3 on HLA DR+ T cells showed a negative association with both pain-related datasets. CD33 on basophils and SSC-A on CD8+ T cells showed a positive association. Sensitivity analyses showed no significant abnormalities. Conclusion: This study systematically identified immune cell phenotypes causally associated with EC and highlighted key lipid mediators underlying these effects. The core immune cell phenotypes and lipids are not only associated with EC risk but also show consistent genetic associations with typical EC-related pain symptoms, suggesting the existence of a co-regulatory network. These findings provide new insights into the mechanism and combined intervention of EC-related pain. Keywords: esophageal cancer, immune cell phenotypes, Mendelian randomization, mediating factor, lipid metabolites, chest pain