{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T21:22:23Z","timestamp":1788556943687,"version":"build-2803163510"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T00:00:00Z","timestamp":1719360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Guangzhou Science and Technology Project","award":["2023A04J0593"],"award-info":[{"award-number":["2023A04J0593"]}]},{"name":"Guangzhou Science and Technology Project","award":["202201010880"],"award-info":[{"award-number":["202201010880"]}]},{"name":"Guangzhou Science and Technology Project","award":["2023B03J0067"],"award-info":[{"award-number":["2023B03J0067"]}]},{"name":"Guangzhou Science and Technology Project","award":["2023A04J1184"],"award-info":[{"award-number":["2023A04J1184"]}]},{"name":"Plan on Enhancing Scientific Research in GMU"},{"name":"Science and Technology Development Fund of Macau","award":["FDCT\/0009\/2023\/RIC"],"award-info":[{"award-number":["FDCT\/0009\/2023\/RIC"]}]},{"DOI":"10.13039\/501100004733","name":"University of Macau","doi-asserted-by":"publisher","award":["MYRG2022-00143-FHS"],"award-info":[{"award-number":["MYRG2022-00143-FHS"]}],"id":[{"id":"10.13039\/501100004733","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004733","name":"University of Macau","doi-asserted-by":"publisher","award":["MYRG-GRG2023-00158-FHS-UMDF"],"award-info":[{"award-number":["MYRG-GRG2023-00158-FHS-UMDF"]}],"id":[{"id":"10.13039\/501100004733","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102860"],"award-info":[{"award-number":["82102860"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by insidious onset and rapid progression, with limited treatment choices. One treatment modality, chimeric antigen receptor (CAR)-modified natural killer (NK) cell immunotherapy, has shown promise for various cancers. However, the treatment efficacy of CAR-NK cells for HCC remain inferior. In this study, we developed two glypican-3 (GPC3)-specific CAR-NK-92 cell lines (GPC3-CAR-NK) and explored their antitumor efficacy for the treatment of HCC. Significant levels of cytokine production and in vitro cytotoxicity were produced following co-culture of GPC3+ HCC cells with the developed GPC3-CAR-NK cells. GC33-G2D-NK cells with NK cell-specific signaling domains showed better activation and killing abilities than GC33-CD28-NK cells containing T-cell-specific signaling domains. Moreover, GC33-G2D-NK cells efficiently eliminated tumors in cell-derived xenograft and patient-derived xenograft mouse models. In an abdominal metastasis model, intraperitoneally delivered GC33-G2D-NK cells showed better antitumor ability than intravenously injected cells. Finally, the combination of microwave ablation (MWA) with GC33-G2D-NK cell administration showed greater CAR-NK infiltration and tumor regression in ablated tumors than monotherapy alone. These findings indicate that administration of GPC3-CAR-NK cells may be a potential strategy for the treatment of HCC, and regional delivery or their combination with MWA may optimize their efficacy against HCC and may have translational value.<\/jats:p>","DOI":"10.1093\/jleuko\/qiae144","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T14:59:32Z","timestamp":1719413972000},"source":"Crossref","is-referenced-by-count":18,"title":["Development of glypican-3-specific chimeric antigen receptor-modified natural killer cells and optimization as a therapy for hepatocellular carcinoma"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1161-7463","authenticated-orcid":false,"given":"Bihui","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080 ,","place":["China"]},{"name":"Department of Guangdong Provincial Key Laboratory of Pathogenesis and Precision Prevention of Heart Disease , Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510100 ,","place":["China"]},{"name":"Department of Radiology, Central Laboratory, The Second Affiliated Hospital, Guangzhou Medical University , Guangzhou 510260 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 119074 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080 ,","place":["China"]},{"name":"Department of Guangdong Provincial Key Laboratory of Pathogenesis and Precision Prevention of Heart Disease , Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510100 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Guangdong Provincial and Guangzhou Municipal Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University , Guangzhou 511436 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinkui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080 ,","place":["China"]},{"name":"Department of Guangdong Provincial Key Laboratory of Pathogenesis and Precision Prevention of Heart Disease , Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510100 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotao","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080 ,","place":["China"]},{"name":"Department of Guangdong Provincial Key Laboratory of Pathogenesis and Precision Prevention of Heart Disease , Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510100 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Central Laboratory, The Second Affiliated Hospital, Guangzhou Medical University , Guangzhou 510260 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5969-6407","authenticated-orcid":false,"given":"Qi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, MoE Frontiers Science Center for Precision Oncology, University of Macau , Macau SAR 999078 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University , Guangzhou 510080 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manting","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Central Laboratory, The Second Affiliated Hospital, Guangzhou Medical University , Guangzhou 510260 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,6,26]]},"reference":[{"issue":"3","key":"2025021510165756600_qiae144-B1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","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"},{"issue":"1","key":"2025021510165756600_qiae144-B2","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/hep.29086","article-title":"AASLD guidelines for the treatment of hepatocellular carcinoma","volume":"67","author":"Heimbach","year":"2017","journal-title":"Hepatology"},{"issue":"6","key":"2025021510165756600_qiae144-B3","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1159\/000509424","article-title":"Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition)","volume":"9","author":"Zhou","year":"2021","journal-title":"Liver Cancer"},{"issue":"3","key":"2025021510165756600_qiae144-B4","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update","volume":"76","author":"Reig","year":"2022","journal-title":"J Hepatol"},{"issue":"6382","key":"2025021510165756600_qiae144-B5","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1126\/science.aar6711","article-title":"CAR t cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science"},{"key":"2025021510165756600_qiae144-B6","doi-asserted-by":"publisher","first-page":"102975","DOI":"10.1016\/j.ebiom.2020.102975","article-title":"CAR-NK cells: a promising cellular immunotherapy for cancer","volume":"59","author":"Xie","year":"2020","journal-title":"EBioMedicine"},{"issue":"4","key":"2025021510165756600_qiae144-B7","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1002\/jlb.5ma0122-467r","article-title":"CAR NK-92 cells targeting DLL3 kill effectively small cell lung cancer cells in vitro and in vivo","volume":"112","author":"Liu","year":"2022","journal-title":"J Leukoc Biol."},{"issue":"14","key":"2025021510165756600_qiae144-B8","doi-asserted-by":"publisher","first-page":"3850","DOI":"10.7150\/ijbs.64630","article-title":"Development of mesothelin-specific CAR NK-92 cells for the treatment of gastric cancer","volume":"17","author":"Cao","year":"2021","journal-title":"Int J Biol Sci."},{"issue":"1","key":"2025021510165756600_qiae144-B9","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.bbrc.2020.01.053","article-title":"Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer","volume":"524","author":"Cao","year":"2020","journal-title":"Biochem Biophys Res Commun."},{"key":"2025021510165756600_qiae144-B10","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.3389\/fimmu.2020.01965","article-title":"Use of cell and genome modification technologies to generate improved \u201coff-the-shelf\u201d CAR T and CAR NK cells","volume":"11","author":"Morgan","year":"2020","journal-title":"Front Immunol"},{"issue":"6","key":"2025021510165756600_qiae144-B11","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.1172\/jci85309","article-title":"CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients","volume":"126","author":"Turtle","year":"2016","journal-title":"J Clin Invest"},{"issue":"1","key":"2025021510165756600_qiae144-B12","doi-asserted-by":"publisher","first-page":"275","DOI":"10.3748\/wjg.v22.i1.275","article-title":"Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma","volume":"22","author":"Yukihiro","year":"2016","journal-title":"World J Gastroenterol"},{"key":"2025021510165756600_qiae144-B13","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3389\/fonc.2019.00248","article-title":"Next-Generation cancer immunotherapy targeting glypican-3","volume":"9","author":"Shimizu","year":"2019","journal-title":"Front Oncol"},{"issue":"4","key":"2025021510165756600_qiae144-B14","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1016\/j.ymthe.2021.01.006","article-title":"A bispecific antibody targeting GPC3 and CD47 induced enhanced antitumor efficacy against dual antigen-expressing HCC","volume":"29","author":"Du","year":"2021","journal-title":"Mol Ther"},{"issue":"1","key":"2025021510165756600_qiae144-B15","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s13045-021-01083-5","article-title":"Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy","volume":"14","author":"Gong","year":"2021","journal-title":"J Hematol Oncol"},{"issue":"10","key":"2025021510165756600_qiae144-B16","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1097\/CAD.0b013e32833f5d68","article-title":"Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization","volume":"21","author":"Nakano","year":"2010","journal-title":"Anticancer Drugs."},{"issue":"1","key":"2025021510165756600_qiae144-B17","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s13045-021-01128-9","article-title":"IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin","volume":"14","author":"Pang","year":"2021","journal-title":"J Hematol Oncol."},{"issue":"2","key":"2025021510165756600_qiae144-B18","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.stem.2018.06.002","article-title":"Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity","volume":"23","author":"Li","year":"2018","journal-title":"Cell Stem Cell"},{"issue":"1","key":"2025021510165756600_qiae144-B19","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1146\/annurev-immunol-020711-075005","article-title":"Controlling natural killer cell responses: integration of signals for activation and inhibition","volume":"31","author":"Long","year":"2013","journal-title":"Annu Rev Immunol."},{"issue":"1","key":"2025021510165756600_qiae144-B20","doi-asserted-by":"publisher","first-page":"11686","DOI":"10.1038\/ncomms11686","article-title":"Stepwise phosphorylation of p65 promotes NF-\u03baB activation and NK cell responses during target cell recognition","volume":"7","author":"Kwon","year":"2016","journal-title":"Nat Commun."},{"issue":"261","key":"2025021510165756600_qiae144-B21","doi-asserted-by":"publisher","first-page":"261ra151","DOI":"10.1126\/scitranslmed.3010162","article-title":"Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity","volume":"6","author":"Adusumilli","year":"2014","journal-title":"Sci Transl Med."},{"issue":"3","key":"2025021510165756600_qiae144-B22","doi-asserted-by":"publisher","first-page":"339","DOI":"10.3109\/02656736.2015.1127434","article-title":"Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis","volume":"32","author":"Facciorusso","year":"2016","journal-title":"Int J Hyperthermia."},{"issue":"25","key":"2025021510165756600_qiae144-B23","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.4254\/wjh.v7.i25.2578","article-title":"Microwave ablation of hepatocellular carcinoma","volume":"7","author":"Poggi","year":"2015","journal-title":"World J Hepatol."},{"key":"2025021510165756600_qiae144-B24","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/nrc3672","article-title":"Thermal ablation of tumours: biological mechanisms and advances in therapy","volume":"14","author":"Chu","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"2025021510165756600_qiae144-B25","doi-asserted-by":"publisher","first-page":"992232","DOI":"10.3389\/fimmu.2022.992232","article-title":"Preclinical and clinical studies of CAR-NK-cell therapies for malignancies","volume":"13","author":"Li","year":"2022","journal-title":"Front Immunol."}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jleukbio\/advance-article-pdf\/doi\/10.1093\/jleuko\/qiae144\/58689223\/qiae144.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/117\/2\/qiae144\/58689223\/qiae144.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/117\/2\/qiae144\/58689223\/qiae144.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,15]],"date-time":"2025-02-15T10:17:11Z","timestamp":1739614631000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/doi\/10.1093\/jleuko\/qiae144\/7699666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,26]]},"references-count":25,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2,13]]}},"URL":"https:\/\/doi.org\/10.1093\/jleuko\/qiae144","relation":{},"ISSN":["1938-3673"],"issn-type":[{"value":"1938-3673","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,2]]},"published":{"date-parts":[[2024,6,26]]},"article-number":"qiae144"}}