APOE-associated lipid-handling macrophages in hepatocellular carcinoma: ligand–receptor communication and host Apoe-linked myeloid remodeling

Background Hepatocellular 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. Methods We 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. Results HCC 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 cell infiltration, whereas tumor-cell Apoe knockdown did not significantly affect tumor volume or tumor weight in immunodeficient mice. In the Nras-Myc liver tumor model, Apoe deficiency reduced tumor burden and proliferative activity and was accompanied by a shift in tumor macrophage and monocyte programs away from lipid-processing and phagolysosomal activity toward inflammatory chemokine-associated activity. In lipid-loaded bone marrow-derived macrophages, Apoe deficiency increased neutral lipid accumulation. Conclusion This study links APOE -associated macrophage lipid handling to inferred ligand–receptor communication and host Apoe -linked microenvironmental remodeling in HCC. These findings highlight an APOE -linked myeloid lipid-handling program as a potential component of immune microenvironmental remodeling during HCC development.