{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:10:12Z","timestamp":1793398212934,"version":"4.5.0"},"reference-count":75,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T00:00:00Z","timestamp":1716768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non\u2010alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti\u2010tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide\u2010related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA\/B\u2010NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane\u2010bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA\u2010mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA\/B\u2010NKG2D\u2010based or NK cell\u2010based immunotherapy for HCC.<\/jats:p>","DOI":"10.1111\/jgh.16584","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T04:58:10Z","timestamp":1716785890000},"page":"1717-1727","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma"],"prefix":"10.1111","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5120-5300","authenticated-orcid":false,"given":"Seung Kak","family":"Shin","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal medicine, Gachon University Gil Medical Center, College of Medicine Gachon University  Incheon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sooyeon","family":"Oh","sequence":"additional","affiliation":[{"name":"Chaum Life Center, School of Medicine CHA University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su\u2010Kyung","family":"Chun","sequence":"additional","affiliation":[{"name":"Chaum Life Center, School of Medicine CHA University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Ji","family":"Ahn","sequence":"additional","affiliation":[{"name":"Center for Research and Development CHA Advanced Research Institute  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung\u2010Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Research and Development CHA Advanced Research Institute  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayun","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Medicine CHA University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hogyeong","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Medicine CHA University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongwoo","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Medicine CHA University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk Pyo","family":"Shin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA Bundang Medical Center CHA University  Seongnam South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jooho","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA Bundang Medical Center CHA University  Seongnam South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6566-1382","authenticated-orcid":false,"given":"Young Kul","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Korea University Ansan Hospital  Ansan South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-014-1000-9"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2005.05.026"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.5045\/br.2015.50.3.126"},{"key":"e_1_2_11_5_1","first-page":"48","article-title":"Immunotherapy of hepatocellular carcinoma: unique challenges and clinical opportunities","volume":"1","author":"Pardee AD","year":"2012","journal-title":"Onco Targets Ther"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.42"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpg.2008.11.015"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2009.10.007"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-823098"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.04.014"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aohep.2020.03.001"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008660"},{"key":"e_1_2_11_13_1","first-page":"2","article-title":"NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient","author":"Tobin LM","year":"2017","journal-title":"JCI Insight"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02180"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0230307"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0251-7"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23253"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.08.019"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2013.10.010"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1069"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2691"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.09.034"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26115"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.01.032"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.10.5423"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086927"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2014.867947"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22452"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23456"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030745"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044743"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2019.0010n"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.03.003"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2006.tb00292.x"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21419"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.10.055"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1146"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2010.211136"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22335"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2667"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01112"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.06.017"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.8.4098"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00859.x"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502439102"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30235"},{"key":"e_1_2_11_47_1","article-title":"TIGIT(+) TIM\u20103(+) NK cells are correlated with NK cell exhaustion and disease progression in patients with hepatitis B virus\u2010related hepatocellular carcinoma","volume":"10","author":"Yu L","year":"2021","journal-title":"Onco Targets Ther"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12040926"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2019.11.003"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2023.0125"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.209"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0062"},{"key":"e_1_2_11_53_1","article-title":"PD\u2010L1 blockade enhances anti\u2010tumor efficacy of NK cells","volume":"7","author":"Oyer JL","year":"2018","journal-title":"Onco Targets Ther"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-2788"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13128"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-010-0944-2"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095951"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2010.00893.x"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2017.07.001"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2520"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31615"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.14029"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/1559-0275-8-9"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1505"},{"key":"e_1_2_11_65_1","first-page":"3123","article-title":"Loss of expression of MHC class I\u2010related chain A (MICA) is a frequent event and predicts poor survival in patients with hepatocellular carcinoma","volume":"7","author":"Zhang J","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.12.051"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3182948452"},{"key":"e_1_2_11_68_1","article-title":"Adjuvant immunotherapy with autologous cytokine\u2010induced killer cells for hepatocellular carcinoma","volume":"148","author":"Lee JH","year":"2015","journal-title":"Gastroenterology"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.5732\/cjc.009.10580"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2009.02121.x"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.3727\/096368911X627589"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.4172\/2155\u20109899.1000376"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123583"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00286"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902000"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3558"}],"container-title":["Journal of Gastroenterology and Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jgh.16584","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T21:41:11Z","timestamp":1746049271000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jgh.16584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,27]]},"references-count":75,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1111\/jgh.16584"],"URL":"https:\/\/doi.org\/10.1111\/jgh.16584","archive":["Portico"],"relation":{},"ISSN":["0815-9319","1440-1746"],"issn-type":[{"value":"0815-9319","type":"print"},{"value":"1440-1746","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,27]]},"assertion":[{"value":"2023-11-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}