{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:25:05Z","timestamp":1787034305497,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Alcohol-associated hepatocellular carcinoma (A-HCC) shows more aggressive progression and has a poorer prognosis than nonalcohol-associated HCC (NA-HCC), but the underlying tumor microenvironment (TME) heterogeneity remains poorly characterized. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from two A-HCC patients, constructing the first single-cell transcriptomic profile of human A-HCC. This dataset was integrated with public NA-HCC scRNA-seq data to compare cellular composition, functional states, and intercellular communication. Both HCC subtypes displayed immunosuppressive TME features, which were significantly more pronounced in A-HCC. Specifically, A-HCC tumors showed greater enrichment of regulatory T cells (Tregs) with enhanced suppressive function, anti-inflammatory macrophage polarization, and more severe CD8\n                    <jats:sup>+<\/jats:sup>\n                    T and NK cell depletion and dysfunction with reduced metabolic activity. Malignant hepatocytes in A-HCC exhibited increased copy-number variation, epithelial-mesenchymal transition (EMT), stemness, proliferation, and drug resistance associated gene signature scores. Cell-cell communication analysis further suggested A-HCC-specific upregulation of immunosuppressive signaling pathways (LTA\/LTB, TGF-\u03b2, LGALS9-HAVCR2) that reinforce this pro-tumorigenic ecosystem. A Treg-derived gene signature from A-HCC was associated with worse overall survival in independent TCGA cohorts. This first comprehensive single-cell comparison uncovers a coordinated immunosuppressive and malignant ecosystem in A-HCC that may be distinct from NA-HCC, providing a mechanistic framework to understand its aggressive clinical behavior and to identify potential etiology-targeted therapeutic strategies. Despite the limited sample size, this study provides the first single-cell resource for A-HCC and lays the foundation for future large-scale validation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1882068","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:36:03Z","timestamp":1787031363000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell transcriptomic profile unveils distinct immune ecosystems in alcohol- and nonalcohol-associated hepatocellular carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Huan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of 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