Plasma metabolites mediate the effects of circulating immune cell phenotypes on prostate cancer: A 2-step Mendelian randomization study.

Prior research suggested the potential correlation between circulating immune cell phenotypes and prostate cancer (PCa). However, it remains unclear whether the correlation can be mediated by plasma metabolites. We performed a bidirectional 2-sample, 2-step Mendelian randomization (MR) study mainly utilizing the inverse variance weighted method to examine the causal role of circulating immunophenotypes on PCa and explore the mediation effect of plasma metabolites in the pathway from immunophenotypes to PCa. MR analyses revealed that 7 circulating immune cell phenotypes and 9 plasma metabolites were significantly related to the risk of PCa. Notably, the mediation MR analysis revealed that X-12100 levels accounted for 10.5% of the decreased risk of PCa associated with CD4 + CD8dim AC in TBNK panel, and X-24418 levels accounted for 11.8% of the elevated risk of PCa related to FSC-A on granulocyte in cDC panel. Our study established a causal relationship between immunophenotypes and PCa, and unveiled the mediating role of plasma metabolites in this association. Meanwhile, we emphasized the notable impact of the immune-metabolite axis on PCa, and immune cells may promote or inhibit tumor progression by influencing metabolite levels, providing a novel insight for studying the pathogenic mechanisms of PCa.