{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:09:21Z","timestamp":1792699761279,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR071711"],"award-info":[{"award-number":["RS-2022-NR071711"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2026-25477439"],"award-info":[{"award-number":["RS-2026-25477439"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2022-NR071711"],"award-info":[{"award-number":["RS-2022-NR071711"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2026-25477439"],"award-info":[{"award-number":["RS-2026-25477439"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Ginsenoside Rh2 (Rh2), a bioactive metabolite of Panax ginseng, has documented anticancer effects, but its role in cancer\u2013immune crosstalk remains incompletely defined. Thus, we aimed to investigate the role of Rh2 in hepatocellular carcinoma (HCC) cells and immune regulation. Methods: We used a co-culture system of murine Hepa1-6 hepatocellular carcinoma cells or nonmalignant AML12 hepatocytes with primary splenocytes to model cancer\u2013immune interactions during Rh2 exposure. Readouts included cell viability, nuclear morphology, and multiparameter flow cytometry. Results: In a co-culture system of Hepa1-6 cells and splenocytes, Rh2 decreased bulk cell viability and increased apoptosis in Hepa1-6 cells. CD8+ T cells exhibited enhanced effector features, with increased CD107a and IFN-\u03b3 expression following Rh2 treatment. Rh2 reduced PD-L1 expression on Hepa1-6 cells and splenocytes, and PD-1 expression on CD8+ T cells. Rh2 also reduced TGF-\u03b21 and IL-6 levels in both Hepa1-6 cells and splenocytes, and decreased IL-10 levels in splenocytes. This was accompanied by a reduction in CD4+CD25+FOXP3+ regulatory T cells (Tregs). Conclusions: In a physiologically relevant cancer\u2013immune context, Rh2 reprograms suppressive interactions by enhancing CD8+ T cell effector function, dampening PD-L1\/PD-1 signaling, and reducing key immunosuppressive cytokines and Tregs. These coordinated effects position Rh2 as a candidate multi-target immunomodulatory agent for enhancing anticancer immunity.<\/jats:p>","DOI":"10.3390\/nu18142224","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:40:09Z","timestamp":1783525209000},"page":"2224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ginsenoside Rh2 Enhances CD8+ T Cell-Mediated Anticancer Immunity in Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Jinbum","family":"Park","sequence":"first","affiliation":[{"name":"Division of Food and Nutrition, Chonnam National University, Gwangju 61186, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-0611","authenticated-orcid":false,"given":"Inae","family":"Jeong","sequence":"additional","affiliation":[{"name":"Human Ecology Research Institute, Chonnam National University, Gwangju 61186, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8180-6214","authenticated-orcid":false,"given":"Anna","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea"},{"name":"K-Food Research Center, Jeonbuk National University, Jeonju 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8338-2571","authenticated-orcid":false,"given":"Ok-Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Food and Nutrition, Chonnam National University, Gwangju 61186, Republic of Korea"},{"name":"Human Ecology Research Institute, Chonnam National University, Gwangju 61186, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.7570\/jomes23052","article-title":"Metabolic dysfunction-associated steatotic liver disease (MASLD): A state-of-the-art review","volume":"32","author":"Chan","year":"2023","journal-title":"J. Obes. Metab. Syndr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.tem.2024.02.007","article-title":"Current status and future trends of the global burden of MASLD","volume":"35","author":"Miao","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bai, Y., Chen, D., Cheng, C., Li, Z., Chi, H., Zhang, Y., Zhang, X., Tang, S., Zhao, Q., and Ang, B. (2022). Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.950536"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.17998\/jlc.20.1.1","article-title":"Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma","volume":"20","author":"Yu","year":"2020","journal-title":"J. Liver Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fasano, R., Shadbad, M.A., Brunetti, O., Argentiero, A., Calabrese, A., Nardulli, P., Calbi, R., Baradaran, B., and Silvestris, N. (2021). Immunotherapy for Hepatocellular Carcinoma: New Prospects for the Cancer Therapy. Life, 11.","DOI":"10.3390\/life11121355"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13045-022-01282-8","article-title":"Immunosuppressive cells in cancer: Mechanisms and potential therapeutic targets","volume":"15","author":"Tie","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41571-022-00601-9","article-title":"Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics","volume":"19","author":"Yamaguchi","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1053\/j.gastro.2020.09.031","article-title":"Steatohepatitis impairs T-cell-directed immunotherapies against liver tumors in mice","volume":"160","author":"Heinrich","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s44276-024-00038-w","article-title":"Impact of underlying liver disease on unresectable HCC treated with immune checkpoint inhibitors","volume":"2","author":"Wu","year":"2024","journal-title":"BJC Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.trecan.2020.02.022","article-title":"Turning cold into hot: Firing up the tumor microenvironment","volume":"6","author":"Duan","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106076","DOI":"10.1016\/j.phrs.2022.106076","article-title":"Future directions for the discovery of natural product-derived immunomodulating drugs: An IUPHAR positional review","volume":"177","author":"Wainwright","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.jgr.2021.12.007","article-title":"Ginsenosides are active ingredients in Panax ginseng with immunomodulatory properties from cellular to organismal levels","volume":"46","author":"You","year":"2022","journal-title":"J. Ginseng Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jgr.2020.02.004","article-title":"Pharmacological potential of ginseng and its major component ginsenosides","volume":"45","author":"Ratan","year":"2021","journal-title":"J. Ginseng Res."},{"key":"ref_16","first-page":"179","article-title":"Anticancer effects of ginsenoside Rh2: A systematic review","volume":"15","author":"He","year":"2022","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, Y.S., Chen, C., Zhang, S.Y., Li, Y., and Jin, Y.H. (2021). (20S)-Ginsenoside Rh2 inhibits STAT3\/VEGF signaling by targeting annexin A2. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179289"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113912","DOI":"10.1016\/j.biopha.2022.113912","article-title":"Role of ginsenoside Rh2 in tumor therapy and tumor microenvironment immunomodulation","volume":"156","author":"Sun","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rong, Y., Jin, D., Wu, W., Lou, W., Wang, D., Kuang, T., Ni, X., and Qin, X. (2009). Induction of protective and therapeutic anti-pancreatic cancer immunity using a reconstructed MUC1 DNA vaccine. BMC Cancer, 9.","DOI":"10.1186\/1471-2407-9-191"},{"key":"ref_20","first-page":"19","article-title":"The role of PD-1\/PD-L1 signaling pathway in cancer pathogenesis and treatment: A systematic review","volume":"10","author":"Sabaghian","year":"2024","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0076-6879(87)51006-0","article-title":"Liver cell lines","volume":"151","author":"Darlington","year":"1987","journal-title":"Methods Enzymol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1073\/pnas.91.2.674","article-title":"Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha","volume":"91","author":"Wu","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Marino, J., Paster, J., and Benichou, G. (2016). Allorecognition by T lymphocytes and allograft rejection. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00582"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"R921","DOI":"10.1016\/j.cub.2020.06.081","article-title":"The tumor microenvironment","volume":"30","author":"Anderson","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth","volume":"41","author":"Joyce","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1146\/annurev.immunol.16.1.111","article-title":"CD40 and CD154 in cell-mediated immunity","volume":"16","author":"Grewal","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1126\/science.8097337","article-title":"IL-12: Initiation cytokine for cell-mediated immunity","volume":"260","author":"Scott","year":"1993","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cellimm.2008.08.007","article-title":"Relationship between CD107a expression and cytotoxic activity","volume":"254","author":"Aktas","year":"2009","journal-title":"Cell. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1128\/CDLI.8.3.628-631.2001","article-title":"Gamma interferon expression in CD8+ T cells is a marker for circulating cytotoxic T lymphocytes that recognize an HLA A2-restricted epitope of human cytomegalovirus phosphoprotein pp65","volume":"8","author":"Ghanekar","year":"2001","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6686","DOI":"10.1073\/pnas.1913940117","article-title":"CD29 identifies IFN-\u03b3\u2013producing human CD8+ T cells with an increased cytotoxic potential","volume":"117","author":"Nicolet","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ai, L., Xu, A., and Xu, J. (2020). Roles of PD-1\/PD-L1 Pathway: Signaling, Cancer, and Beyond, Springer. Advances in Experimental Medicine and Biology.","DOI":"10.1007\/978-981-15-3266-5_3"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.molcel.2019.09.030","article-title":"Mechanisms controlling PD-L1 expression in cancer","volume":"76","author":"Cha","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1111\/cas.14069","article-title":"Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?","volume":"110","author":"Ohue","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Stijlemans, B., Korf, H., De Baetselier, P., Brys, L., Van Ginderachter, J.A., Magez, S., and De Trez, C. (2020). Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008170"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.jhep.2023.12.015","article-title":"IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction","volume":"80","author":"Shiri","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.cell.2008.07.025","article-title":"TGF-\u03b2: A master of all T cell trades","volume":"134","author":"Li","year":"2008","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.4049\/jimmunol.1402898","article-title":"IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1","volume":"195","author":"Hsu","year":"2015","journal-title":"J. Immunol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/14\/2224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T04:13:33Z","timestamp":1783743213000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/14\/2224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["nu18142224"],"URL":"https:\/\/doi.org\/10.3390\/nu18142224","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]}}}