{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T20:16:35Z","timestamp":1794428195128,"version":"4.9.1"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with limited curative options for advanced disease. Natural Killer (NK) cells are critical innate immune effectors, but their anti-tumor function is severely compromised by the immunosuppressive tumor immune microenvironment (TIME), particularly through transforming growth factor-beta (TGF-\u03b2). This study investigates the pivotal role of TGF-\u03b2 signaling in modulating NK cell phenotypes and functions within the HCC TIME.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>to comprehensively assess TGF-\u03b2 pathway activation and its impact on NK cells, tumor-infiltrating lymphocytes (TILs) and liver-infiltrating lymphocytes (LILs) were isolated from HCC patients undergoing curative resection. Phenotypic and functional analyses were performed, along with functional restoration experiments targeting TGF-\u03b2 signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Tumor-infiltrating NK cells (TINKs) exhibited significant activation of both canonical (SMAD-dependent) and non-canonical (TAK1\/p38 MAPK) TGF-\u03b2 signaling, with a predominance of the non-canonical pathway. This activation was associated with the emergence of an ILC1-like NK subset (CD103\n                      <jats:sup>+<\/jats:sup>\n                      \/CD49a\n                      <jats:sup>+<\/jats:sup>\n                      ), which was nearly absent in non-tumor liver tissue. These ILC1-like cells maintained strong cytokine production and expressed high levels of inhibitory receptors (PD-1, TIM-3, TIGIT), whereas conventional NK cells (cNKs; CD103\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/CD49a\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/CD9\n                      <jats:sup>\u2212<\/jats:sup>\n                      ) were functionally impaired. Notably, blocking TGF-\u03b2 receptor binding and SMAD3 activation restored cNK functionality.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>our findings suggest that while non-canonical TGF-\u03b2 signaling drives phenotypic reprogramming and contributes to NK cell dysfunction, canonical SMAD-dependent signaling remains a key therapeutic target for functional restoration. These results highlight the dual role of TGF-\u03b2 in immune modulation and suggest that targeted pathway inhibition could enhance innate anti-tumor responses, opening new avenues for combination therapies in HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1651129","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:28:43Z","timestamp":1762324123000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["TGF-\u03b2-driven NK Cells plasticity in hepatocellular carcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Valentina","family":"Reverberi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Montali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vecchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Pelagatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Doselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Farina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Olivani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Economopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Dalla Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diletta","family":"Laccabue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ferraglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia","family":"Penna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Fisicaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Boni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Missale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2023.0070","article-title":"The latest global burden of liver cancer: A past and present threat","volume":"29","author":"Oh","year":"2023","journal-title":"Clin Mol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32740","article-title":"The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma","volume":"77","author":"Donne","year":"2023","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cells10061332","article-title":"Natural killer cells and T cells in hepatocellular carcinoma and viral hepatitis: current status and perspectives for future immunotherapeutic approaches","volume":"10","author":"Kalathil","year":"2021","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202582","article-title":"Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors","volume":"190","author":"Cerdeira","year":"2013","journal-title":"J Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/cells10030614","article-title":"Intratumor regulatory noncytotoxic NK cells in patients with hepatocellular carcinoma","volume":"10","author":"Zecca","year":"2021","journal-title":"Cells"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0757","article-title":"Accumulation of tumor-infiltrating CD49a+ NK cells correlates with poor prognosis for human hepatocellular carcinoma","volume":"7","author":"Sun","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e22680","article-title":"High CD49a+ NK cell infiltrate is associated with poor clinical outcomes in Hepatocellular Carcinoma","volume":"9","author":"Zecca","year":"2023","journal-title":"Heliyon"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6248590","article-title":"Altered NKp30, NKp46, NKG2D, and DNAM-1 expression on circulating NK cells is associated with tumor progression in human gastric cancer","volume":"2018","author":"Han","year":"2018","journal-title":"J Immunol Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-018-2121-4","article-title":"An IL-15 superagonist\/IL-15R\u03b1 fusion complex protects and rescues NK cell-cytotoxic function from TGF-\u03b21-mediated immunosuppression","volume":"67","author":"Fujii","year":"2018","journal-title":"Cancer Immunol Immunother"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00293","article-title":"Role of distinct natural killer cell subsets in anticancer response","volume":"8","author":"Stabile","year":"2017","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1593\/neo.121758","article-title":"The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer","volume":"15","author":"Bruno","year":"2013","journal-title":"Neoplasia"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900866","article-title":"TGF-\u03b2 and IL-15 synergize through MAPK pathways to drive the conversion of human NK cells to an innate lymphoid cell 1-like phenotype","volume":"204","author":"Hawke","year":"2020","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"3841","DOI":"10.1038\/s41467-019-11632-9","article-title":"Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells","volume":"10","author":"Marquardt","year":"2019","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2023.2233402","article-title":"Accumulation of tissue-resident natural killer cells, innate lymphoid cells, and CD8+ T cells towards the center of human lung tumors","volume":"12","author":"Brownlie","year":"2023","journal-title":"Oncoimmunology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e2026271118","DOI":"10.1073\/pnas.2026271118","article-title":"Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis","volume":"118","author":"Ducimeti\u00e8re","year":"2021","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B16","doi-asserted-by":"publisher","first-page":"eabm9043","DOI":"10.1126\/scitranslmed.abm9043","article-title":"NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity","volume":"14","author":"Kirchhammer","year":"2022","journal-title":"Sci Transl Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.875072","article-title":"Targeting stress sensor kinases in hepatocellular carcinoma-infiltrating human NK cells as a novel immunotherapeutic strategy for liver cancer","volume":"13","author":"Zecca","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"R23","DOI":"10.1186\/ar3247","article-title":"Modulation of transforming growth factor beta signalling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: involvement of Sp1 in both early and late response cells to transforming growth factor beta","volume":"13","author":"Baug\u00e9","year":"2011","journal-title":"Arthritis Res Ther"},{"key":"B19","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.canlet.2018.07.001","article-title":"Tumor necrosis factor-\u03b1 promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells","volume":"434","author":"Jing","year":"2018","journal-title":"Cancer Lett"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.12.7335","article-title":"Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients","volume":"172","author":"Lee","year":"2004","journal-title":"J\u00a0Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1651129\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:28:44Z","timestamp":1762324124000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1651129\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":20,"alternative-id":["10.3389\/fimmu.2025.1651129"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129","relation":{"has-part":[{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129.s001","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129.s002","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129.s003","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129.s004","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129.s005","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2025.1651129.s006","asserted-by":"subject"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,5]]},"article-number":"1651129"}}