Abstract

BackgroundHepatocellular carcinoma (HCC) arises in the liver, an organ with active lipid metabolism, and is accompanied by marked myeloid-cell remodeling. Whether lipid-handling macrophage states are enriched in HCC and how they relate to candidate ligand–receptor communication and tumor microenvironmental remodeling remain unclear.MethodsWe analyzed paired tumor and adjacent liver single-cell transcriptomic data from 10 HCC patients. Tumor-associated lipid-handling candidates were screened using immune-cell composition, metabolic pathway activity, and tumor-upregulated lipid-related gene programs, with APOE prioritized for downstream analysis. Myeloid reclustering, module scoring, and CellChat analysis were used to characterize APOE-positive macrophages and infer APOE-positive macrophage-centered candidate communication. Hepa1–6 subcutaneous tumor models, an Nras-Myc-driven liver tumor model, mouse single-cell transcriptomics, and bone marrow-derived macrophage lipid-loading experiments were used to assess host Apoe deficiency, tumor-cell Apoe perturbation, and macrophage neutral lipid accumulation.ResultsHCC tumors showed altered immune-cell composition and immune-metabolic pathway activity compared with adjacent liver tissues. Among tumor-upregulated lipid-related candidates, APOE was prioritized because of its tumor-associated expression, consistent ranking across lipid-related screening strategies, and functional relevance to lipoprotein and cholesterol handling. APOE-positive macrophages were enriched in tumors and displayed lipid-routing, cholesterol-handling, endolysosomal, and redox-adaptive programs. CellChat analysis identified candidate ligand–receptor interactions involving APOE-positive macrophages, including an APOE–TREM2-related incoming interaction and SPP1–integrin/CD44 outgoing interactions. In the immunocompetent Hepa1–6 model, host Apoe deficiency attenuated tumor growth and was accompanied by reduced vascularization and increased CD8-positive