{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:27:46Z","timestamp":1786429666187,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82361148722"],"award-info":[{"award-number":["82361148722"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2308600, 2024YFE0213800"],"award-info":[{"award-number":["2023YFC2308600, 2024YFE0213800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007847","name":"Natural Science Foundation of Jilin Province","doi-asserted-by":"publisher","award":["YDZJ202601ZYTS644"],"award-info":[{"award-number":["YDZJ202601ZYTS644"]}],"id":[{"id":"10.13039\/100007847","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n 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\u2013receptor communication and tumor microenvironmental remodeling remain unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n 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\n APOE<\/jats:italic>\n prioritized for downstream analysis. Myeloid reclustering, module scoring, and CellChat analysis were used to characterize\n APOE<\/jats:italic>\n -positive macrophages and infer\n APOE<\/jats:italic>\n -positive macrophage-centered candidate communication. Hepa1\u20136 subcutaneous tumor models, an\n Nras-Myc<\/jats:italic>\n -driven liver tumor model, mouse single-cell transcriptomics, and bone marrow-derived macrophage lipid-loading experiments were used to assess host\n Apoe<\/jats:italic>\n deficiency, tumor-cell\n Apoe<\/jats:italic>\n perturbation, and macrophage neutral lipid accumulation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n HCC tumors showed altered immune-cell composition and immune-metabolic pathway activity compared with adjacent liver tissues. Among tumor-upregulated lipid-related candidates,\n APOE<\/jats:italic>\n was prioritized because of its tumor-associated expression, consistent ranking across lipid-related screening strategies, and functional relevance to lipoprotein and cholesterol handling.\n APOE<\/jats:italic>\n -positive macrophages were enriched in tumors and displayed lipid-routing, cholesterol-handling, endolysosomal, and redox-adaptive programs. CellChat analysis identified candidate ligand\u2013receptor interactions involving\n APOE<\/jats:italic>\n -positive macrophages, including an\n APOE<\/jats:italic>\n \u2013\n TREM2<\/jats:italic>\n -related incoming interaction and\n SPP1<\/jats:italic>\n \u2013integrin\/\n CD44<\/jats:italic>\n outgoing interactions. In the immunocompetent Hepa1\u20136 model, host\n Apoe<\/jats:italic>\n deficiency attenuated tumor growth and was accompanied by reduced vascularization and increased CD8-positive cell infiltration, whereas tumor-cell\n Apoe<\/jats:italic>\n knockdown did not significantly affect tumor volume or tumor weight in immunodeficient mice. In the\n Nras-Myc<\/jats:italic>\n liver tumor model,\n Apoe<\/jats:italic>\n 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,\n Apoe<\/jats:italic>\n deficiency increased neutral lipid accumulation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study links\n APOE<\/jats:italic>\n -associated macrophage lipid handling to inferred ligand\u2013receptor communication and host\n Apoe<\/jats:italic>\n -linked microenvironmental remodeling in HCC. These findings highlight an\n APOE<\/jats:italic>\n -linked myeloid lipid-handling program as a potential component of immune microenvironmental remodeling during HCC development.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1902143","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:35:08Z","timestamp":1786426508000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["APOE-associated lipid-handling macrophages in hepatocellular carcinoma: ligand\u2013receptor communication and host Apoe-linked myeloid remodeling"],"prefix":"10.3389","volume":"17","author":[{"given":"Tong","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University","place":["Changchun, China"]},{"name":"Jilin Provincial Key Laboratory of Metabolic Liver Diseases, The First Hospital of Jilin 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Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University","place":["Changchun, China"]},{"name":"Jilin Provincial Key Laboratory of Metabolic Liver Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]},{"name":"China\u2013Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University","place":["Changchun, China"]},{"name":"Jilin Provincial Key Laboratory of Metabolic Liver Diseases, The First Hospital of Jilin University, Jilin University","place":["Changchun, China"]},{"name":"China\u2013Singapore Belt and Road Joint Laboratory on Liver Disease Research, 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