{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:50:55Z","timestamp":1790610655162,"version":"4.1.0"},"reference-count":85,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central role. This review synthesizes human-focused evidence (tissues, blood, clinical cohorts, and single-cell\/spatial studies) through September 2025 to define how Tregs are recruited, maintained, and functionally deployed in HCC. Across datasets, intratumoral effector-like Tregs (eTregs) expressing ICOS, CTLA-4, CCR8, and CD39\/CD73 accumulate within tumors and co-localize with exhausted cytotoxic PD-1hi CD8+ T cells and suppressive myeloid cells. Recruitment is driven mainly by CCL20\u2013CCR6 and CCL22\/CCL17\u2013CCR4 signaling, while CCR8 marks highly suppressive tumor-resident Tregs. Their persistence is supported by TGF-\u03b2, IL-10, IL-35, adenosine signaling, IL-2 sequestration, and metabolic adaptation. Spatial biomarkers, including ICOS+\/CCR8+ eTreg density and CD8:Treg ratios, associate with prognosis and emerging immunotherapy responses. Etiology further shapes immune architecture: HBV-related HCC often forms Treg-exhausted T-cell niches around viral antigens, whereas MASLD\/MASH promotes stromal and metabolic barriers that may reduce PD-(L)1 efficacy. Current treatments (PD-(L)1 blockade with anti-VEGF or CTLA-4, and some TKIs) intersect with Treg biology, while emerging strategies targeting CCR8, CCR4, ICOS, or the adenosine pathway aim to selectively disrupt intratumoral eTreg networks. This review underscores that an etiology-aware, spatial-biomarker framework may guide the integration of selective Treg targeting with PD-(L)1-based therapies in HCC.<\/jats:p>","DOI":"10.3390\/ijms27104630","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:53:24Z","timestamp":1779371604000},"page":"4630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications"],"prefix":"10.3390","volume":"27","author":[{"given":"Dimitris","family":"Liapopoulos","sequence":"first","affiliation":[{"name":"Biopathological Laboratory, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"},{"name":"Biopathological Laboratory, Athens Medical Group, Psychiko Clinic, Antersen 1, 115 25 Psychiko, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-7905","authenticated-orcid":false,"given":"Panagiotis","family":"Sarantis","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27 Athens, Greece"},{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"},{"name":"Institute of Molecular Medicine and Biomedical Research, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Zogas","sequence":"additional","affiliation":[{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni-Myrto","family":"Trifylli","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine-GI-Liver Unit, General Hospital \u2018Hippokratio\u2019, Medical School, National and Kapodistrian University of Athens, Vasilissis Sofias 114, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaleia-Eleftheria","family":"Bousou","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Laiko General Hospital, Agiou Thoma 17, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Kamitaki","sequence":"additional","affiliation":[{"name":"Blood Bank, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7560-0575","authenticated-orcid":false,"given":"Ioanna A.","family":"Anastasiou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Kokkali","sequence":"additional","affiliation":[{"name":"Oncology Unit, Second Department of Medicine, University of Athens, Hippocratio General Hospital of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sotiris","family":"Mavromatis","sequence":"additional","affiliation":[{"name":"Biopathological Laboratory, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos","family":"Koustas","sequence":"additional","affiliation":[{"name":"Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8118-7190","authenticated-orcid":false,"given":"Ioannis","family":"Elefsiniotis","sequence":"additional","affiliation":[{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Biniari","sequence":"additional","affiliation":[{"name":"Biopathological Laboratory, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1369-8201","authenticated-orcid":false,"given":"Michalis V.","family":"Karamouzis","sequence":"additional","affiliation":[{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"},{"name":"Institute of Molecular Medicine and Biomedical Research, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1053\/j.gastro.2019.02.049","article-title":"Surveillance for hepatocellular carcinoma: Current best practice and future direction","volume":"157","author":"Kanwal","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1146\/annurev.immunol.021908.132629","article-title":"The liver as a lymphoid organ","volume":"27","author":"Crispe","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/eji.200636435","article-title":"Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells","volume":"37","author":"Wang","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/eji.202149318","article-title":"Helios is a marker, not a driver, of human Treg stability","volume":"52","author":"Lam","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1002\/eji.200737594","article-title":"DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells","volume":"37","author":"Baron","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/eji.200838105","article-title":"DNA methylation controls Foxp3 gene expression","volume":"38","author":"Polansky","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.immuni.2009.03.019","article-title":"Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor","volume":"30","author":"Miyara","year":"2009","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2019.10.003","article-title":"Landscape and dynamics of single immune cells in hepatocellular carcinoma","volume":"179","author":"Zhang","year":"2019","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/j.cell.2017.05.035","article-title":"Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing","volume":"169","author":"Zheng","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1038\/s41467-021-24010-1","article-title":"Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma","volume":"12","author":"Ho","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1053\/j.gastro.2007.03.102","article-title":"Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients","volume":"132","author":"Fu","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s13045-021-01207-x","article-title":"Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma","volume":"14","author":"Lu","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_17","first-page":"EVIDoa2100070","article-title":"Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"1","author":"Lau","year":"2022","journal-title":"NEJM Evid."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"35056","DOI":"10.1038\/srep35056","article-title":"Regulatory T cells, especially ICOS(+) FOXP3(+) regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival","volume":"6","author":"Tu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.immuni.2016.10.021","article-title":"Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells","volume":"45","author":"Arrigoni","year":"2016","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.immuni.2016.10.032","article-title":"Regulatory T cells exhibit distinct features in human breast cancer","volume":"45","author":"Plitas","year":"2016","journal-title":"Immunity"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1084\/jem.20062512","article-title":"Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression","volume":"204","author":"Deaglio","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.jhep.2014.04.027","article-title":"TGF-\u03b2-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells","volume":"61","author":"Carambia","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/hep.24029","article-title":"Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-\u03b2","volume":"53","author":"Zhang","year":"2011","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.4049\/jimmunol.1201937","article-title":"Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid","volume":"190","author":"Dunham","year":"2013","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/bjc.2016.47","article-title":"Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection","volume":"114","author":"Fu","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.cmet.2016.12.018","article-title":"Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments","volume":"25","author":"Angelin","year":"2017","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ccell.2022.01.001","article-title":"Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments","volume":"40","author":"Kumagai","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E6546","DOI":"10.1073\/pnas.1720113115","article-title":"Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth","volume":"115","author":"Pacella","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41590-019-0589-5","article-title":"CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors","volume":"21","author":"Wang","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41586-019-1785-z","article-title":"Bile acid metabolites control T\u209517 and Treg cell differentiation","volume":"576","author":"Hang","year":"2019","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nature12726","article-title":"Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation","volume":"504","author":"Arpaia","year":"2013","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/eji.200839040","article-title":"Neuropilin-1 is not a marker of human Foxp3+ Treg","volume":"39","author":"Milpied","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Akimova, T., Beier, U.H., Wang, L., Levine, M.H., and Hancock, W.W. (2011). Helios expression is a marker of T cell activation and proliferation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024226"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chen, K.J., Lin, S.Z., Zhou, L., Xie, H.Y., Zhou, W.H., Taki-Eldin, A., and Zheng, S.S. (2011). Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024671"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jhep.2021.08.029","article-title":"Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B","volume":"76","author":"Gao","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12362","DOI":"10.1038\/s41598-017-10267-4","article-title":"Up-regulation of chemokine receptor CCR4 is associated with human hepatocellular carcinoma malignant behavior","volume":"7","author":"Cheng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13046-025-03286-x","article-title":"CCR8 antagonist suppresses liver cancer progression via turning tumor-infiltrating Tregs into less immunosuppressive phenotype","volume":"44","author":"Tian","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1159\/000438631","article-title":"Hepatocellular carcinoma cells induce regulatory T cells and lead to poor prognosis via production of transforming growth factor-\u03b21","volume":"38","author":"Wang","year":"2016","journal-title":"Cell Physiol. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.molimm.2021.02.014","article-title":"IL-10 derived from hepatocarcinoma cells improves human induced regulatory T cells function via JAK1\/STAT5 pathway in tumor microenvironment","volume":"133","author":"Zhang","year":"2021","journal-title":"Mol. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/cei.13535","article-title":"Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma","volume":"203","author":"Liu","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e4989","DOI":"10.1097\/MD.0000000000004989","article-title":"Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection","volume":"95","author":"Cai","year":"2016","journal-title":"Medicine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"100959","DOI":"10.1016\/j.jhepr.2023.100959","article-title":"Adenosine A2a receptor inhibition increases the anti-tumor efficacy of anti-PD-1 treatment in murine hepatobiliary cancers","volume":"6","author":"Myojin","year":"2024","journal-title":"JHEP Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.4049\/jimmunol.178.4.2132","article-title":"High IFN-\u03b3 production of individual CD8 T lymphocytes is controlled by CD152 (CTLA-4)","volume":"178","author":"Pandiyan","year":"2007","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1158\/0008-5472.CAN-12-3381","article-title":"Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality","volume":"73","author":"Kalathil","year":"2013","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1159\/000525239","article-title":"ICOS-positive regulatory T cells in hepatocellular carcinoma: The perspective from digital pathology analysis","volume":"100","author":"Lu","year":"2022","journal-title":"Oncology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1200\/JCO.2006.09.4565","article-title":"Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection","volume":"25","author":"Gao","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1111\/cas.16247","article-title":"Prognostic and therapeutic potential of imbalance between PD-1+CD8 and ICOS+Treg cells in advanced HBV-HCC","volume":"115","author":"Yan","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1186\/s40425-019-0814-7","article-title":"PD1(Hi) CD8(+) T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma","volume":"7","author":"Ma","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1097\/HEP.0000000000000369","article-title":"Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC","volume":"78","author":"You","year":"2023","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.immuni.2015.01.006","article-title":"The transcription factor NFAT promotes exhaustion of activated CD8(+) T cells","volume":"42","author":"Martinez","year":"2015","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A transcription factors limit CAR T cell function in solid tumours","volume":"567","author":"Chen","year":"2019","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.cell.2017.08.004","article-title":"NF-kappaB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer","volume":"170","author":"Oh","year":"2017","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","article-title":"NASH limits anti-tumour surveillance in immunotherapy-treated HCC","volume":"592","author":"Pfister","year":"2021","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ccell.2018.02.010","article-title":"Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies","volume":"33","author":"Furness","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1073\/pnas.1801524115","article-title":"Anti-CTLA-4 therapy requires an Fc domain for efficacy","volume":"115","author":"Ingram","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1084\/jem.20130579","article-title":"Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma","volume":"210","author":"Simpson","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1056\/NEJMoa1717002","article-title":"Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma","volume":"379","author":"Meyer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1002\/hep.32023","article-title":"Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma","volume":"74","author":"Torrens","year":"2021","journal-title":"Hepatology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e204564","DOI":"10.1001\/jamaoncol.2020.4564","article-title":"Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial","volume":"6","author":"Yau","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1200\/JCO.2011.37.3472","article-title":"Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: A multicenter phase II study","volume":"30","author":"Ishida","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e001749","DOI":"10.1136\/jitc-2020-001749","article-title":"Therapeutic depletion of CCR8(+) tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy","volume":"9","author":"Dombrecht","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e2114282119","DOI":"10.1073\/pnas.2114282119","article-title":"CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory","volume":"119","author":"Kidani","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s10238-024-01362-8","article-title":"Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody","volume":"24","author":"Roider","year":"2024","journal-title":"Clin. Exp. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2141007","DOI":"10.1080\/2162402X.2022.2141007","article-title":"Differential expression of CCR8 in tumors versus normal tissue allows specific depletion of tumor-infiltrating T regulatory cells by GS-1811, a novel Fc-optimized anti-CCR8 antibody","volume":"11","author":"Weaver","year":"2022","journal-title":"Oncoimmunology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1200\/JCO.2021.39.15_suppl.2626","article-title":"KY1044 to target the ICOS pathways inducing intratumoral Treg depletion and agonism of effector T cells: Preliminary pharmacodynamic markers from a phase 1\/2 multicenter trial","volume":"39","author":"Lin","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e005471","DOI":"10.1136\/jitc-2022-005471","article-title":"First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors","volume":"10","author":"Hamid","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2167189","DOI":"10.1080\/19420862.2023.2167189","article-title":"The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy","volume":"15","author":"Claus","year":"2023","journal-title":"MAbs"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1038\/s41467-018-05072-0","article-title":"Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors","volume":"9","author":"Duhen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S1470-2045(18)30351-6","article-title":"Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial","volume":"19","author":"Zhu","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Elkord, E. (2016). Helios Should Not Be Cited as a Marker of Human Thymus-Derived Tregs. Commentary: Helios(+) and Helios(-) Cells Coexist within the Natural FOXP3(+) T Regulatory Cell Subset in Humans. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00276"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4594","DOI":"10.1038\/s41467-022-32283-3","article-title":"A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma","volume":"13","author":"Lu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.annonc.2024.02.005","article-title":"Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"35","author":"Sangro","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e8746","DOI":"10.15252\/msb.20188746","article-title":"Current best practices in single-cell RNA-seq analysis: A tutorial","volume":"15","author":"Luecken","year":"2019","journal-title":"Mol. Syst. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cels.2018.11.005","article-title":"Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data","volume":"8","author":"Wolock","year":"2019","journal-title":"Cell Syst."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","article-title":"DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors","volume":"8","author":"McGinnis","year":"2019","journal-title":"Cell Syst."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e1175794","DOI":"10.1080\/2162402X.2016.1175794","article-title":"Cancer cell-derived IL-1alpha induces CCL22 and the recruitment of regulatory T cells","volume":"5","author":"Wiedemann","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1200\/JCO.23.01462","article-title":"Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma","volume":"42","author":"Sangro","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1111\/hepr.12513","article-title":"Fatal reactivation of hepatitis B virus infection in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab","volume":"45","author":"Ifuku","year":"2015","journal-title":"Hepatol. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1158\/0008-5472.CAN-20-3585","article-title":"Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models","volume":"81","author":"Campbell","year":"2021","journal-title":"Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"LBA432","DOI":"10.1200\/JCO.2024.42.3_suppl.LBA432","article-title":"EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization","volume":"42","author":"Lencioni","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12943-023-01733-x","article-title":"CD39\/CD73\/A2AR pathway and cancer immunotherapy","volume":"22","author":"Xia","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1007\/s00262-023-03430-6","article-title":"First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors","volume":"72","author":"Bendell","year":"2023","journal-title":"Cancer Immunol. Immunother."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4630\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T05:34:56Z","timestamp":1779687296000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":85,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104630"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104630","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,21]]}}}