{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:27:50Z","timestamp":1786429670257,"version":"build-2736575974"},"reference-count":42,"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\/100017949","name":"Health Commission of Shanxi Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017949","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lipids serve as both metabolic substrates and signaling mediators that critically regulate immune cell fate, function, tolerance, and intercellular communication. In hepatocellular carcinoma (HCC), it remains unclear how intratumoral linoleic acid (LA) allocation between desaturation and oxidative catabolism influences immunometabolic remodeling and post-transplant recurrence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Multi-omics profiling was conducted in a liver transplant-associated HCC cohort using paired tumor\/non-tumor tissues and serum samples. The intratumoral lipid milieu (C4\u2013C24 fatty acids) was quantified by targeted gas chromatography, whereas lipid\u2013immune programs were resolved by single-nucleus RNA sequencing (snRNA-seq) integrated with targeted transcriptomic profiling. Key immune phenotypes and candidate genes were validated by serum inflammatory mediator profiling, flow cytometric lymphocyte immunophenotyping, spatially resolved tissue assays, and qRT\u2013PCR. LA perturbation experiments provided functional support\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      Fatty acid profiling revealed that non-recurrent tumors were characterized by a higher intratumoral LA\/AA ratio and a lower estimated \u03946-desaturation index than recurrent tumors, whereas recurrent tumors exhibited a higher estimated \u03946-desaturation index than their matched distant non-tumor liver tissues. snRNA-seq identified fatty acid catabolism as the most prominently downregulated metabolic pathway in recurrent tumors; malignant-cell analysis further highlighted EHHADH and ACSL3 as key genes involved in recurrence-associated lipid metabolic remodeling.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , exogenous LA-BSA increased ROS accumulation and reduced SPP1 and NECTIN2 expression in HCC cells. Cell\u2013cell communication analysis showed enhanced tumor\u2013Treg signaling in recurrence, with VISTA- and CD80-related networks shifting from Kupffer cells toward SPP1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages and Tregs. Peripheral and tissue immunophenotyping showed reduced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and higher IL-10 in recurrent tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Multi-omics analyses indicate that, in primary pre-transplant HCC, post-transplant recurrence is associated with an imbalance between a higher estimated \u03946-desaturation index and attenuated oxidative catabolism-related features of linoleic acid, accompanied by Treg-associated immunosuppressive remodeling. These findings provide a biologically informed framework for post-transplant recurrence risk stratification and further translational investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1862165","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:35:29Z","timestamp":1786426529000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Linoleic acid metabolic reprogramming is linked to immunometabolic remodeling and post-transplant recurrence risk in hepatocellular carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Ruixin","family":"Zhang","sequence":"first","affiliation":[{"name":"The First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery & Liver Transplantation Center, The First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Gao","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqian","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Center, Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Key Laboratory of Prevention and Treatment of Liver Injury and Digestive System Neoplasms, Provincial Committee of the Medical and Health","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.01.033","article-title":"Global epidemiology and genetics of hepatocellular carcinoma","volume":"164","author":"Toh","year":"2023","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00245-6","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000001467","article-title":"Development and comprehensive validation of a predictive prognosis model for very early HCC recurrence within one year after curative resection: a multicenter cohort study","volume":"110","author":"Liu","year":"2024","journal-title":"Int J Surg"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000005514","article-title":"Post-recurrence survival after liver transplantation for hepatocellular carcinoma","volume":"109","author":"Maspero","year":"2025","journal-title":"Transplantation"},{"key":"B5","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.jhep.2024.06.018","article-title":"Histological predictors of aggressive recurrence of hepatocellular carcinoma after liver resection","volume":"81","author":"Fuster","year":"2024","journal-title":"J Hepatol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3724\/abbs.2023068","article-title":"Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3\/p53\/NRF2 axis in colorectal cancer cells","volume":"55","author":"Wu","year":"2023","journal-title":"Acta Biochim Biophys Sin"},{"key":"B7","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.cmet.2023.02.013","article-title":"Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity","volume":"35","author":"Nava Lauson","year":"2023","journal-title":"Cell Metab"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1021\/acs.chemrev.3c00520","article-title":"The octadecanoids: Synthesis and bioactivity of 18-carbon oxygenated fatty acids in mammals, bacteria, and fungi","volume":"125","author":"Revol-Cavalier","year":"2025","journal-title":"Chem Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2024.108612","article-title":"Pathological and pharmacological functions of the metabolites of polyunsaturated fatty acids mediated by cyclooxygenases, lipoxygenases, and cytochrome P450s in cancers","volume":"256","author":"Meng","year":"2024","journal-title":"Pharmacol Ther"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.09.003","article-title":"Targeting ACSLs to modulate ferroptosis and cancer immunity","volume":"36","author":"Lin","year":"2025","journal-title":"Trends Endocrinol Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf6710","article-title":"Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland","volume":"9","author":"Witt","year":"2023","journal-title":"Sci Adv"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-025-01420-5","article-title":"LncRNA Gm35585 transcriptionally activates the peroxidase EHHADH against diet-induced fatty liver","volume":"57","author":"Jin","year":"2025","journal-title":"Exp Mol Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2024.101276","article-title":"Oxylipin profiling for clinical research: Current status and future perspectives","volume":"95","author":"Parchem","year":"2024","journal-title":"Prog Lipid Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-024-10703-4","article-title":"Immunosuppression in adult liver transplant recipients: a 2024 update from the Italian Liver Transplant Working Group","volume":"18","author":"Manzia","year":"2024","journal-title":"Hepatol Int"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ueg2.70078","article-title":"Recurrence of hepatocellular carcinoma after liver transplantation: The blind spot of HCC management","volume":"13","author":"Ningarhari","year":"2025","journal-title":"United Eur Gastroenterol J"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.01.004","article-title":"Principles of regulatory T cell function","volume":"56","author":"Dikiy","year":"2023","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.immuni.2024.01.019","article-title":"Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells","volume":"57","author":"Ding","year":"2024","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.cell.2025.11.034","article-title":"Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity","volume":"189","author":"Gu","year":"2026","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"11034","DOI":"10.1038\/s41467-025-66168-y","article-title":"Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma","volume":"16","author":"Lu","year":"2025","journal-title":"Nat Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adg8817","article-title":"Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos","volume":"9","author":"Ma","year":"2024","journal-title":"Sci Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s40246-024-00624-6","article-title":"Deep learning-based pathway-centric approach to characterize recurrent hepatocellular carcinoma after liver transplantation","volume":"18","author":"To","year":"2024","journal-title":"Hum Genomics"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032116","article-title":"Dihomo-\u03b3-linolenic acid (20:3n-6)-metabolism, derivatives, and potential significance in chronic inflammation","volume":"24","author":"Mustonen","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2022.101165","article-title":"Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions","volume":"86","author":"Dyall","year":"2022","journal-title":"Prog Lipid Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2024.159564","article-title":"Recent advances on the physiological and pathophysiological roles of polyunsaturated fatty acids and their biosynthetic pathway","volume":"1870","author":"Lee-Okada","year":"2025","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3908","DOI":"10.1038\/s41467-025-59184-5","article-title":"ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27","volume":"16","author":"Wang","year":"2025","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2424251122","article-title":"Prostaglandin E2-EP2\/EP4 signaling induces the tumor-infiltrating Treg phenotype for tumor growth","volume":"122","author":"Matsuura","year":"2025","journal-title":"Proc Natl Acad Sci USA"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1016\/j.cell.2024.01.030","article-title":"Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis","volume":"187","author":"Qiu","year":"2024","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s13045-023-01498-2","article-title":"Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics","volume":"16","author":"Jin","year":"2023","journal-title":"J Hematol Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s40170-022-00290-z","article-title":"ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma","volume":"10","author":"Klasson","year":"2022","journal-title":"Cancer Metab"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20230041","article-title":"The biochemistry and physiology of long-chain dicarboxylic acid metabolism","volume":"480","author":"Ranea-Robles","year":"2023","journal-title":"Biochem J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102764","article-title":"The mammalian peroxisomal membrane is permeable to both GSH and GSSG - Implications for intraperoxisomal redox homeostasis","volume":"63","author":"Ferreira","year":"2023","journal-title":"Redox Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI179874","article-title":"TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models","volume":"135","author":"Jiang","year":"2024","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/6177553","article-title":"Ginsenoside Rh4 inhibits colorectal cancer cell proliferation by inducing ferroptosis via autophagy activation","volume":"2022","author":"Wu","year":"2022","journal-title":"Evid Based Complement Alternat Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adm8660","article-title":"Targeting conserved TIM3+VISTA+ tumor-associated macrophages overcomes resistance to cancer immunotherapy","volume":"10","author":"Vanmeerbeek","year":"2024","journal-title":"Sci Adv"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.12.008","article-title":"VISTA: A mediator of quiescence and a promising target in cancer immunotherapy","volume":"42","author":"Yuan","year":"2021","journal-title":"Trends Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1711015","article-title":"SPP1+ macrophages in tumor immunosuppression: mechanisms and therapeutic implications","volume":"16","author":"Wang","year":"2025","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023739118","article-title":"Treg-expressed CTLA-4 depletes CD80\/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells","volume":"118","author":"Tekguc","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"B38","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13045-024-01549-2","article-title":"Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives","volume":"17","author":"Shen","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1602877","article-title":"Regulation of the immune microenvironment and immunotherapy after liver transplantation","volume":"16","author":"Lan","year":"2025","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41698-024-00564-3","article-title":"Single-cell and spatial analyses revealed the co-location of cancer stem cells and SPP1+ macrophage in hypoxic region that determines the poor prognosis in hepatocellular carcinoma","volume":"8","author":"Fan","year":"2024","journal-title":"NPJ Precis Oncol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1441730","article-title":"The Nectin family ligands, PVRL2 and PVR, in cancer immunology and immunotherapy","volume":"15","author":"Murakami","year":"2024","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s12943-025-02274-1","article-title":"Modulating lipid metabolism by nanoparticles (NPs)-mediated ACSL3 silencing to inhibit hepatocellular carcinoma growth and metastasis","volume":"24","author":"Huang","year":"2025","journal-title":"Mol Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1862165\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:35:30Z","timestamp":1786426530000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1862165\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2026.1862165"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1862165","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"1862165"}}