{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:52:00Z","timestamp":1792176720765,"version":"4.4.0"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82350105"],"award-info":[{"award-number":["82350105"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371533"],"award-info":[{"award-number":["32371533"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>CD226 plays a vital role in NK cell cytotoxicity, interacting with its ligands on tumor targets. Acute myeloid leukemia (AML) cells have developed mechanisms to escape NK cell cytotoxicity, including inducing downregulation of CD226 on NK cells. Induced pluripotent stem cell -derived NK (iPSC-NK) cells offer an important source of standardized off-the-shelf NK cell therapy to treat AML patients. In this study, we engineered iPSC-NK cells with CD226 to assess the ability of killing AML cells. iPSC-NK cells engineered with CD226 have a typical NK cell phenotype and demonstrate improved anti-AML activity and multiple cytokines releasing at low effector-to-target ratios. Transcriptomic analysis revealed upregulation of immune effector function pathways associated with cytotoxicity and immune activation in CD226-overexpression iPSC-NK cells. In an AML xenograft model, mice treated with CD226 overexpression iPSC-NK cells exhibited significantly reduced leukemia burden, prolonged survival, decreased systemic inflammation compared to those treated with Control iPSC-NK cells. Overall, our study provided evidence that iPSC derived-NK cells engineered with CD226 represent a promising candidate for off-the-shelf immunotherapy, particularly in AML and other CD226 ligand-expressing malignancies.<\/jats:p>","DOI":"10.1186\/s40164-025-00686-9","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T09:17:43Z","timestamp":1751879863000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["iPSC-derived NK cells engineered with CD226 effectively control acute myeloid leukemia"],"prefix":"10.1186","volume":"14","author":[{"given":"Runze","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binyan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"issue":"1","key":"686_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40164-024-00592-6","volume":"14","author":"R Huang","year":"2025","unstructured":"Huang R, Wang X, Yan H, Tan X, Ma Y, Wang M, et al. Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed\/refractory AML: preclinical evaluation and phase I trial. Exp Hematol Oncol. 2025;14(1):1.","journal-title":"Exp Hematol Oncol"},{"issue":"12","key":"686_CR2","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1093\/intimm\/dxab085","volume":"33","author":"A Shibuya","year":"2021","unstructured":"Shibuya A, Shibuya K. DNAM-1 versus TIGIT: competitive roles in tumor immunity and inflammatory responses. Int Immunol. 2021;33(12):687\u201392.","journal-title":"Int Immunol"},{"issue":"5","key":"686_CR3","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/0092-8674(89)90690-9","volume":"56","author":"CL Mendelsohn","year":"1989","unstructured":"Mendelsohn CL, Wimmer E, Racaniello VR. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. 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Blood. 2016;127(26):3341\u20139.","journal-title":"Blood"},{"issue":"25","key":"686_CR6","doi-asserted-by":"publisher","first-page":"3855","DOI":"10.1182\/blood-2013-10-532531","volume":"123","author":"V Bachanova","year":"2014","unstructured":"Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 2014;123(25):3855\u201363.","journal-title":"Blood"},{"issue":"1","key":"686_CR7","first-page":"4","volume":"1","author":"H Zhu","year":"2019","unstructured":"Zhu H, Kaufman DS. Engineered human pluripotent stem cell-derived natural killer cells: the next frontier for cancer immunotherapy. Blood Sci (Baltimore Md). 2019;1(1):4\u201311.","journal-title":"Blood Sci (Baltimore Md)"},{"issue":"1","key":"686_CR8","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s40164-024-00583-7","volume":"13","author":"P Yao","year":"2024","unstructured":"Yao P, Liu YG, Huang G, Hao L, Wang R. The development and application of chimeric antigen receptor natural killer (CAR-NK) cells for cancer therapy: current state, challenges and emerging therapeutic advances. Experimental Hematol Oncol. 2024;13(1):118.","journal-title":"Experimental Hematol Oncol"},{"issue":"2","key":"686_CR9","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.stem.2018.06.002","volume":"23","author":"Y Li","year":"2018","unstructured":"Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-Derived natural killer cells engineered with chimeric antigen receptors enhance Anti-tumor activity. Cell Stem Cell. 2018;23(2):181\u201392.","journal-title":"Cell Stem Cell"},{"issue":"2","key":"686_CR10","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.stem.2020.05.008","volume":"27","author":"H Zhu","year":"2020","unstructured":"Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, et al. Metabolic reprograming via deletion of CISH in human iPSC-Derived NK cells promotes in vivo persistence and enhances anti-tumor activity. Cell Stem Cell. 2020;27(2):224\u201337.","journal-title":"Cell Stem Cell"},{"issue":"1","key":"686_CR11","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s13045-023-01455-z","volume":"16","author":"F Meng","year":"2023","unstructured":"Meng F, Zhang S, Xie J, Zhou Y, Wu Q, Lu B, et al. Leveraging CD16 fusion receptors to remodel the immune response for enhancing anti-tumor immunotherapy in iPSC-derived NK cells. 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Methods Mol Biol. 2019;2048:107\u201319.","journal-title":"Methods Mol Biol"}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00686-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-025-00686-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00686-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T09:17:43Z","timestamp":1751879863000},"score":1,"resource":{"primary":{"URL":"https:\/\/ehoonline.biomedcentral.com\/articles\/10.1186\/s40164-025-00686-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":12,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["686"],"URL":"https:\/\/doi.org\/10.1186\/s40164-025-00686-9","relation":{},"ISSN":["2162-3619"],"issn-type":[{"value":"2162-3619","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,7]]},"assertion":[{"value":"5 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at Peking University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"93"}}