Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignant liver tumors worldwide and is associated with a high mortality rate. Methods: In this study, we performed an integrated multi-omics analysis to characterize the immune and metabolic features of the tumor microenvironment (TME) in HCC. Tumor samples from 60 HCC patients were stratified into two groups based on immune activity score, and differentially expressed genes as well as differentially methylated regions were identified between these groups. Results: Our analysis identified key markers including AGXT2 and DPYS (metabolism-related genes) and TNFSF8 (an immune-related gene). Their increased expression, driven by promoter hypomethylation, was linked to distinct TME profiles. Furthermore, single-cell RNA sequencing revealed cell type-specific expression patterns of these genes, and their higher expression levels were correlated with favorable patient prognosis. Conclusions: These findings demonstrate that the interplay between metabolic pathways and epigenetic regulation of immune genes strongly influences the HCC microenvironment and clinical outcomes. The identified genes could serve as promising therapeutic targets, emphasizing the importance of multi-omics approaches in dissecting tumor heterogeneity.