Unveiling the Role of Immune Cells and Plasma Metabolites in Breast Cancer Risk: A Mendelian Randomization and Mediation Analysis

Background: Breast cancer (BC) is the most common cancer worldwide, yet identifying effective therapeutic targets continues to pose challenges. To understand the biological mechanisms driving BC and uncover potential therapeutic strategies, we performed a comprehensive Mendelian randomization (MR) analysis. The objective of this study is to investigate the causal relationships between immune cell phenotypes and BC risk, with a focus on identifying intermediary metabolites involved in these processes. Methods: We conducted MR analysis using genome-wide association study (GWAS) data from publicly available databases, focusing on 731 immune cell traits (n = 3757), 1400 plasma metabolites (n = 8299), and breast cancer (n case = 6188, n control = 182,678). We used a two-step MR approach to examine the potential intermediary role of plasma metabolites in the immune cell-BC relationship. The research employs the inverse variance weighting (IVW) method as its primary approach. To assess potential sources of bias, such as horizontal pleiotropy and heterogeneity, we employed the MR Egger intercept test and the Cochran's Q test, respectively. These rigorous analytical approaches ensured the robustness of our findings. Furthermore, Bayesian colocalization was employed to enhance the accuracy of causal inference and reduce false positives. Results: The IVW method of reverse MR analysis revealed a causal relationship between 20 immune cell traits and BC. Notably, our analysis identified three plasma metabolites as potential mediators in the causal link between immune cells and BC. In particular, vanillic acid glycine partially mediated the relationship between CD28+ CD45RA- CD8dim %CD8dim cells and BC. This suggests that vanillic acid glycine may act as a molecular link, modulating immune cell functions that contribute to BC. Additionally, the pyruvate to N-acetylneuraminate ratio exhibited negative mediation effects involving IgD- CD38dim AC, HLA DR on DC, CD8dim NKT %T cells, and CCR2 on monocytes. The negative mediation implies that this metabolite might inhibit certain immune cell behaviors that would otherwise promote cancer progression. Furthermore, cysteinylglycine disulfide partially mediated the relationship between CD8 on TD CD8br cells and BC, suggesting its involvement in the modulation of CD8 +T cell responses in BC. Key immune cell phenotypes, such as CCR2 on monocytes (odds ratio, ORIVW = 0.969; 95% CI: 0.943-0.996; p = 0.027), IgD- CD38dim AC cells (ORIVW = 1.100; 95% CI: 1.023-1.183; p = 0.009), were highlighted for their significant roles in BC progression. Conclusion: This study shows that vanillic acid glycine levels, the pyruvate to N-acetylneuraminate ratio, and cysteinylglycine disulfide levels can act as mediators in reducing breast cancer risk. These findings support the idea that metabolic pathways and metabolites are crucial in cancer progression, offering insights into potential biomarkers for early detection, treatment assessment, and recurrence prediction, thus paving the way for more personalized clinical approaches.