Causal association of blood metabolites, immune cells, and lung cancer: A mediation Mendelian randomization study

Lung cancer ranks highest in annual mortality among all cancers, and blood metabolites may influence its onset and progression. Our objective is to assess the causal relationships between blood metabolites and both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), while exploring the mediating effects of immune cells. We utilized publicly available genetic data to investigate the potential causal relationships between blood metabolites and NSCLC as well as SCLC using a 2-sample Mendelian randomization (MR) approach. In our primary analysis, we employed the inverse variance weighted (IVW) method and conducted sensitivity analyses and Steiger test to assess the reliability and directionality of the causal relationships. Additionally, we employed a 2-step MR approach to evaluate the mediating role of immune cells in these causal relationships. The IVW method revealed that palmitoylcarnitine levels (metabolon platform) and 4 other blood metabolites are risk factors for NSCLC, while tetrahydrocortisol glucuronide levels and 2 other blood metabolites are protective factors for NSCLC. Additionally, Alpha-hydroxyisovalerate levels and 8 other blood metabolites are risk factors for SCLC, whereas dimethylglycine levels and 3 other blood metabolites are protective factors for SCLC. Furthermore, IgD- CD27- B cell %B cell, CD27 on IgD- CD38dim B cell, and CD3 on Naive CD4+ T cell mediate some of the relationships between blood metabolites and NSCLC. Activated and secreting CD4 regulatory T cell %CD4+ T cell, CD14- CD16- Absolute Count, and IgD on IgD+ CD24+ B cell mediate some of the relationships between blood metabolites and SCLC. There are significant causal relationships between blood metabolites and both NSCLC and SCLC, with some of these relationships mediated by immune cells. This aids us in influencing the role of blood metabolites in lung cancer by intervening with immune cells, thereby providing more avenues for the prevention and treatment of lung cancer.