Genetically Predicted Immune Cell Traits Mediate the Causal Association Between Plasma Metabolites and Colorectal Cancer

<b>Background:</b> Relevant studies have demonstrated that plasma metabolites and immune cell characteristics are closely related to colorectal cancer (CRC). However, the causal relationship among these factors remains unclear, particularly regarding whether immune cell traits mediate the causal link between plasma metabolites and CRC. <b>Methods:</b> This study employed a two-step, two-sample Mendelian randomization (MR) using summary data from genome-wide association studies (GWAS) to assess causal associations between 1,400 plasma metabolites, 731 immune cell traits, and CRC. Additionally, it evaluated the mediating effect of immune cell traits and utilized single-cell RNA sequencing (scRNA-seq) to analyze immune cells infiltration in CRC, assess their metabolic functional changes and their interactions with CRC cells. <b>Results:</b> Univariable two-sample MR analysis revealed causal relationships between 49 plasma metabolites and CRC, as well as between 36 immune cell traits and CRC. Two-step MR analysis revealed that two plasma metabolites (Sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1) and 16α-hydroxy-DHEA-3-sulfate) influence CRC through two immune cell traits (SSC-A on CD14+ monocyte and CD3 on CD28- CD8+ T cell). Among these, SSC-A on CD14+ monocyte exhibited the highest mediating effect proportion, at 11.723%. scRNA-seq analysis further confirmed the increased infiltration of CD28- CD8+ T cells and CD14+ monocytes in CRC, along with upregulated sphingolipid metabolism and steroid biosynthesis. These cells were also found to interact with CRC cells, contributing to tumor initiation and progression. <b>Conclusion:</b> This study provides new evidence for the causal relationship between plasma metabolites and CRC, and it identifies immune factors with potential mediating roles. These findings offer new insights for further exploration of the mechanisms underlying the development of CRC.