Abstract
Background: This study presents a comprehensive investigation into the molecular mechanisms of hepatocellular carcinoma (HCC) through an innovative application of Mendelian randomization (MR) analysis, integrated with immune cell profiling and metabolomic assessment. Methods: Utilizing two-sample Mendelian randomization (TSMR) with data from large-scale GWAS studies, including immune cell profiles from the UK Biobank (n = 1629) and HCC cases from a multi-ethnic meta-analysis (775 cases, 1332 controls), we identified significant causal associations between specific immune cell populations, serum metabolites, and HCC risk. This study employed a multi-omics approach, including Principal Component Analysis (PCA), Gene Set Enrichment Analysis (GSEA), to conduct a comprehensive analysis of the liver cancer TME. Results: Our analysis revealed three immune cell populations significantly associated with HCC development: CD127-expressing CD28 + CDACDB-T cells (OR = 1.31), and unswitched memory B cells measured by both percentage (OR = 1.57) and absolute count (OR = 1.49). We found an increased dispersion of tumor cells in PCA, reflecting adaptive changes due to complex gene regulatory networks. The TYROBP gene was specifically expressed in myeloid cells and enriched in multiple biological pathways. Cell communication analysis revealed significant interactions between T cells and tumor cells. Conclusion: This study provides a comprehensive view of the heterogeneity of the liver cancer TME and reveals the potential roles of key genes and cell types in the development of liver cancer. These findings offer new insights into the molecular mechanisms of liver cancer and may aid in the identification of new therapeutic targets and biomarkers.