M2 macrophages and tumor cells engage in a metabolic feedback loop to drive HCC progression.

Hepatocellular carcinoma (HCC) represents a significant global health challenge due to its molecular heterogeneity and the immunosuppressive nature of its tumor microenvironment (TME). Tumor-associated macrophages (TAMs), particularly the M2-polarized subset, are crucial in HCC progression, contributing to immune evasion, angiogenesis, and metastasis. However, the mechanisms driving TAM reprogramming and their metabolic interactions within the TME remain poorly understood. In this study, we applied single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to identify a novel metabolic-immune axis in HCC. Our findings revealed increased oxidative phosphorylation (OXPHOS) in tumor cells, which correlated with enhanced ribosomal activity in M2 macrophages, suggesting a metabolic coupling between the two. Tumor cells, under elevated OXPHOS, secrete factors that recruit macrophages and promote M2 polarization, thereby reinforcing immune suppression. Further analysis of The Cancer Genome Atlas (TCGA) dataset led to the development of a prognostic model based on OXPHOS-related genes, showing strong predictive power across multiple cohorts. These results suggest a novel OXPHOS-ribosome-M2 polarization axis and offer potential therapeutic targets for immunometabolic therapies in HCC.