Investigating the metabolite-mediated effects of immune cells on squamous lung cancer: a Mendelian randomization analysis

Abstract Background Lung cancer (LC) is a leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) being a significant subtype. Immune cells are critical in tumor surveillance and the immune response, and recent advancements in immune checkpoint inhibitors (ICIs) have enhanced the treatment of non-small cell lung cancer (NSCLC), including LUSC. Metabolites produced during tumor metabolism may influence immune cell function, affecting immune cell proliferation, differentiation, and activation and overall effectiveness. This study aims to explore the causal relationships between metabolite-mediated immune cells and LUSC via Mendelian randomization (MR). Methods Genome-wide association study (GWAS) summary statistics for LUSC were obtained from the International Lung Cancer Consortium (ILCCO), including 3,275 cases and 15,038 controls, with data on 8,893,750 single nucleotide polymorphisms (SNPs). A total of 731 immunophenotypes and 1,400 metabolite GWAS catalogs were analyzed. The study conducted four MR analyses: forward MR analysis with immune cells as the exposure and LUSC as the outcome, positive MR analysis with metabolites as the exposure and LUSC as the outcome, and mediated MR analysis with immune cells as the exposure, metabolites as mediators, and LUSC as the outcome. Sensitivity analyses were performed to ensure the robustness, heterogeneity, and multibiological effects of the findings. Results The analysis revealed that 13 immune cells, including 7 high-risk immune cells and 6 protective immune cells, were significantly correlated with LUSC. Thirteen metabolites were also linked to LUSC, with 2 high-risk and 11 protective metabolites. Mediated MR analysis revealed significant associations between naive-mature B-cell percentage and taurolithocholate 3-sulfate (mediated effect = 0.006, p = 0.0405), the CD4/CD8br ratio and the alpha-ketoglutarate to aspartate ratio (mediated effect = 0.023, p = 0.0121), and the CD4 + percentage of leukocytes and SSC-A on lymphocytes with indolepropionate levels (mediated effect = 0.018, p = 0.0169 and mediated effect=-0.017, p = 0.0162, respectively). Conclusion This study reveals the causal roles of immune cells and metabolites in LUSC via genetic approaches. These findings suggest that specific metabolites mediate the involvement of immune cells in LUSC, providing new insights for therapeutic strategies.