{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:49:26Z","timestamp":1792126166887,"version":"4.4.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":87,"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":["82401978"],"award-info":[{"award-number":["82401978"]}],"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":["82300718"],"award-info":[{"award-number":["82300718"]}],"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":["82301904"],"award-info":[{"award-number":["82301904"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Engineering Research Center of Stem Cells Translational Medicine"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Discov."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recent investigations have indicated that NK cells induced overnight with IL-12\/15\/18 cytokines possess memory-like characteristics (refers as CIML NK, cytokine induced memory-like NK cells), demonstrating enhanced effector function and prolonged persistence. Preclinical studies and very early clinical trials revealed the promising clinical activity of CIML NK cells in the treatment of hematological malignancies, especially acute myelocytic leukemia (AML). However, the current manufacturing method for CIML NK cells do not endow these cells the ability to expand robustly ex vivo. The low production efficiency limits their clinical application. In this study, we established a novel expansion platform for generating memory-like NK cells by first inducing memory properties through stimulation with CD16a, IL-15, and IL-18, followed by a robust expansion phase. This method can effectively and stably expand healthy donor-derived Peripheral NK (PBNK) cells by more than 200-fold within two weeks, with a purity exceeding 95%. Importantly, these ex vivo expanded NK (ExNK) cells exhibited hypomethylated state in the CNS-1 region (Conserved Noncoding Sequence 1) of\n                    <jats:italic>IFNG<\/jats:italic>\n                    gene, stronger metabolic ability, and enhanced effector function when compared to CIML NK cells. Based on these features, we named these expanded NK cells but still possess memory-like characteristics as mExNK (memory-like expanded NK cells). Bulk mRNA-seq further uncovered a high similarity between mExNK and CIML NK cells, with both highly expressing genes being related to proliferation, metabolism, and memory. Mouse tumor models proved that the infused mExNK exhibited longer persistence in vivo and stronger effector functions. Taken together, the method described herein showed an enhanced expansion efficiency for human CIML NK cells and would facilitate their clinic applications in cancer therapy.\n                  <\/jats:p>","DOI":"10.1038\/s41420-026-03260-2","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:45:00Z","timestamp":1784652300000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytokine-induced expandable memory NK cells with significant metabolic, epigenetic remodeling, and persistence properties"],"prefix":"10.1038","volume":"12","author":[{"given":"Hongye","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjia","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2848-1611","authenticated-orcid":false,"given":"Wencheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2592-2106","authenticated-orcid":false,"given":"Qianggang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-7835","authenticated-orcid":false,"given":"Zhiying","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"3260_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13045-020-01014-w","volume":"14","author":"S Liu","year":"2021","unstructured":"Liu S, Galat V, Galat Y, Lee YKA, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol. 2021;14:7.","journal-title":"J Hematol Oncol"},{"key":"3260_CR2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.1198687","volume":"331","author":"E Vivier","year":"2011","unstructured":"Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Sciences. 2011;331:44\u20139.","journal-title":"Sciences"},{"key":"3260_CR3","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nri3799","volume":"15","author":"L Martinet","year":"2015","unstructured":"Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15:243\u201354.","journal-title":"Nat Rev Immunol"},{"key":"3260_CR4","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1007\/s00262-010-0904-3","volume":"59","author":"EG Iliopoulou","year":"2010","unstructured":"Iliopoulou EG, Kountourakis P, Karamouzis MV, Doufexis D, Ardavanis A, Baxevanis CN, et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol, Immunother CII. 2010;59:1781\u20139.","journal-title":"Cancer Immunol, Immunother CII"},{"key":"3260_CR5","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-015-0632-8","volume":"13","author":"N Sakamoto","year":"2015","unstructured":"Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K, Ideno M, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med. 2015;13:277.","journal-title":"J Transl Med"},{"key":"3260_CR6","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1182\/blood.2022016200","volume":"141","author":"MM Berrien-Elliott","year":"2023","unstructured":"Berrien-Elliott MM, Jacobs MT, Fehniger TA. Allogeneic natural killer cell therapy. Blood. 2023;141:856\u201368.","journal-title":"Blood"},{"key":"3260_CR7","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.it.2013.02.005","volume":"34","author":"G Min-Oo","year":"2013","unstructured":"Min-Oo G, Kamimura Y, Hendricks DW, Nabekura T, Lanier LL. Natural killer cells: walking three paths down memory lane. Trends Immunol. 2013;34:251\u20138.","journal-title":"Trends Immunol"},{"key":"3260_CR8","doi-asserted-by":"crossref","first-page":"vlaf083","DOI":"10.1093\/immhor\/vlaf083","volume":"10","author":"S Bryan","year":"2026","unstructured":"Bryan S, Gamage GS, Dey S, Medina-Luna D, Parsons BD, Makrigiannis AP, et al. Peptide-adaptive NK cell memory in the absence of functional TCR genes. Immunohorizons. 2026;10:vlaf083.","journal-title":"Immunohorizons"},{"key":"3260_CR9","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1038\/ni.1953","volume":"11","author":"S Paust","year":"2010","unstructured":"Paust S, Gill HS, Wang BZ, Flynn MP, Moseman EA, Senman B, et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol. 2010;11:1127\u201335.","journal-title":"Nat Immunol"},{"key":"3260_CR10","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/j.0105-2896.2010.00906.x","volume":"235","author":"S Paust","year":"2010","unstructured":"Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev. 2010;235:286\u201396.","journal-title":"Immunol Rev"},{"key":"3260_CR11","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41581-022-00633-5","volume":"19","author":"J Ochando","year":"2023","unstructured":"Ochando J, Mulder WJM, Madsen JC, Netea MG, Duivenvoorden R. Trained immunity - basic concepts and contributions to immunopathology. Nat Rev Nephrol. 2023;19:23\u201337.","journal-title":"Nat Rev Nephrol"},{"key":"3260_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-85960-6","volume":"11","author":"I Terr\u00e9n","year":"2021","unstructured":"Terr\u00e9n I, Orrantia A, Mosteiro A, Vitall\u00e9 J, Zenarruzabeitia O, Borrego F. Metabolic changes of Interleukin-12\/15\/18-stimulated human NK cells. Sci Rep. 2021;11:6472.","journal-title":"Sci Rep"},{"key":"3260_CR13","doi-asserted-by":"crossref","first-page":"e1219009","DOI":"10.1080\/2162402X.2016.1219009","volume":"5","author":"J Ni","year":"2016","unstructured":"Ni J, H\u00f6lsken O, Miller M, Hammer Q, Luetke-Eversloh M, Romagnani C, et al. Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4(+) T cell help. Oncoimmunology. 2016;5:e1219009.","journal-title":"Oncoimmunology"},{"key":"3260_CR14","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1158\/2326-6066.CIR-20-1002","volume":"9","author":"MK Becker-Hapak","year":"2021","unstructured":"Becker-Hapak MK, Shrestha N, McClain E, Dee MJ, Chaturvedi P, Leclerc GM, et al. A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy. Cancer Immunol Res. 2021;9:1071\u201387.","journal-title":"Cancer Immunol Res"},{"key":"3260_CR15","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1186\/s13287-021-02655-5","volume":"12","author":"M Tarannum","year":"2021","unstructured":"Tarannum M, Romee R. Cytokine-induced memory-like natural killer cells for cancer immunotherapy. Stem Cell Res Ther. 2021;12:592.","journal-title":"Stem Cell Res Ther"},{"key":"3260_CR16","doi-asserted-by":"crossref","first-page":"4751","DOI":"10.1182\/blood-2012-04-419283","volume":"120","author":"R Romee","year":"2012","unstructured":"Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, et al. Cytokine activation induces human memory-like NK cells. Blood. 2012;120:4751\u201360.","journal-title":"Blood"},{"key":"3260_CR17","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abm1375","volume":"14","author":"MM Berrien-Elliott","year":"2022","unstructured":"Berrien-Elliott MM, Foltz JA, Russler-Germain DA, Neal CC, Tran J, Gang M, et al. Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. Sci Transl Med. 2022;14:eabm1375.","journal-title":"Sci Transl Med"},{"key":"3260_CR18","doi-asserted-by":"crossref","first-page":"4754","DOI":"10.4049\/jimmunol.1201742","volume":"190","author":"MP Keppel","year":"2013","unstructured":"Keppel MP, Yang L, Cooper MA. Murine NK cell intrinsic cytokine-induced memory-like responses are maintained following homeostatic proliferation. J Immunol. 2013;190:4754\u201362.","journal-title":"J Immunol"},{"key":"3260_CR19","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1182\/blood.2021013972","volume":"139","author":"JJ Bednarski","year":"2022","unstructured":"Bednarski JJ, Zimmerman C, Berrien-Elliott MM, Foltz JA, Becker-Hapak M, Neal CC, et al. Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Blood. 2022;139:1670\u201383.","journal-title":"Blood"},{"key":"3260_CR20","doi-asserted-by":"crossref","first-page":"e154334","DOI":"10.1172\/JCI154334","volume":"132","author":"RM Shapiro","year":"2022","unstructured":"Shapiro RM, Birch GC, Hu G, Vergara Cadavid J, Nikiforow S, Baginska J, et al. Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse. J Clin Invest. 2022;132:e154334.","journal-title":"J Clin Invest"},{"key":"3260_CR21","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1158\/2159-8290.CD-20-0312","volume":"10","author":"MM Berrien-Elliott","year":"2020","unstructured":"Berrien-Elliott MM, Cashen AF, Cubitt CC, Neal CC, Wong P, Wagner JA, et al. Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia. Cancer Discov. 2020;10:1854\u201371.","journal-title":"Cancer Discov"},{"key":"3260_CR22","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.intimp.2012.09.014","volume":"14","author":"X Deng","year":"2012","unstructured":"Deng X, Terunuma H, Nieda M, Xiao W, Nicol A. Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells. Int Immunopharmacol. 2012;14:593\u2013605.","journal-title":"Int Immunopharmacol"},{"key":"3260_CR23","doi-asserted-by":"crossref","first-page":"e20201529","DOI":"10.1084\/jem.20201529","volume":"218","author":"RS Huang","year":"2021","unstructured":"Huang RS, Lai MC, Shih HA, Lin S. A robust platform for expansion and genome editing of primary human natural killer cells. J Exper Med. 2021;218:e20201529.","journal-title":"J Exper Med"},{"key":"3260_CR24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3892\/ijo.2015.3005","volume":"47","author":"X Li","year":"2015","unstructured":"Li X, He C, Liu C, Ma J, Ma P, Cui H, et al. Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21. Int J Oncol. 2015;47:335\u201342.","journal-title":"Int J Oncol"},{"key":"3260_CR25","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1158\/2326-6066.CIR-17-0550","volume":"6","author":"JHW Pahl","year":"2018","unstructured":"Pahl JHW, Koch J, G\u00f6tz JJ, Arnold A, Reusch U, Gantke T, et al. CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells. Cancer Immunol Res. 2018;6:517\u201327.","journal-title":"Cancer Immunol Res"},{"key":"3260_CR26","volume":"12","author":"HK Mishra","year":"2021","unstructured":"Mishra HK, Dixon KJ, Pore N, Felices M, Miller JS, Walcheck B. Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation. Front Immunol. 2021;12:711621.","journal-title":"Front Immunol"},{"key":"3260_CR27","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ymthe.2019.10.009","volume":"28","author":"EJ Pomeroy","year":"2020","unstructured":"Pomeroy EJ, Hunzeker JT, Kluesner MG, Lahr WS, Smeester BA, Crosby MR, et al. A Genetically Engineered Primary Human Natural Killer Cell Platform for Cancer Immunotherapy. Mol Ther. 2020;28:52\u201363.","journal-title":"Mol Ther"},{"key":"3260_CR28","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/35040504","volume":"408","author":"J Parrish-Novak","year":"2000","unstructured":"Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57\u201363.","journal-title":"Nature"},{"key":"3260_CR29","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1007\/s10238-022-00974-2","volume":"23","author":"TV Shman","year":"2023","unstructured":"Shman TV, Vashkevich KP, Migas AA, Matveyenka MA, Lasiukov YA, Mukhametshyna NS, et al. Phenotypic and functional characterisation of locally produced natural killer cells ex vivo expanded with the K562-41BBL-mbIL21 cell line. Clin Exp Med. 2023;23:2551\u201360.","journal-title":"Clin Exp Med"},{"key":"3260_CR30","doi-asserted-by":"crossref","DOI":"10.1002\/iid3.749","volume":"11","author":"L Vidard","year":"2023","unstructured":"Vidard L. 4-1BB and cytokines trigger human NK, \u03b3\u03b4 T, and CD8(+) T cell proliferation and activation, but are not required for their effector functions. Immun Inflamm Dis. 2023;11:e749.","journal-title":"Immun Inflamm Dis"},{"key":"3260_CR31","doi-asserted-by":"crossref","first-page":"115718","DOI":"10.1016\/j.biopha.2023.115718","volume":"168","author":"M Bakhtiyaridovvombaygi","year":"2023","unstructured":"Bakhtiyaridovvombaygi M, Yazdanparast S, Mikanik F, Izadpanah A, Parkhideh S, Shahbaz Ghasabeh A, et al. Cytokine-Induced Memory-Like NK Cells: Emerging strategy for AML immunotherapy. Biomed Pharmacother. 2023;168:115718.","journal-title":"Biomed Pharmacother"},{"key":"3260_CR32","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.bbmt.2014.01.006","volume":"20","author":"JW Leong","year":"2014","unstructured":"Leong JW, Chase JM, Romee R, Schneider SE, Sullivan RP, Cooper MA, et al. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Biol Blood Marrow Transpl. 2014;20:463\u201373.","journal-title":"Biol Blood Marrow Transpl"},{"key":"3260_CR33","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1038\/s41577-019-0139-2","volume":"19","author":"KL O\u2019Brien","year":"2019","unstructured":"O\u2019Brien KL, Finlay DK. Immunometabolism and natural killer cell responses. Nat Rev Immunol. 2019;19:282\u201390.","journal-title":"Nat Rev Immunol"},{"key":"3260_CR34","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.4049\/jimmunol.1501783","volume":"196","author":"SE Keating","year":"2016","unstructured":"Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K, Finlay DK, et al. Metabolic Reprogramming Supports IFN-\u03b3 Production by CD56bright NK Cells. J Immunol. 2016;196:2552\u201360.","journal-title":"J Immunol"},{"key":"3260_CR35","doi-asserted-by":"crossref","first-page":"e0170975","DOI":"10.1371\/journal.pone.0170975","volume":"12","author":"D Nicholas","year":"2017","unstructured":"Nicholas D, Proctor EA, Raval FM, Ip BC, Habib C, Ritou E, et al. Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis. PLoS ONE. 2017;12:e0170975.","journal-title":"PLoS ONE"},{"key":"3260_CR36","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.4049\/jimmunol.173.3.1514","volume":"173","author":"CM Tato","year":"2004","unstructured":"Tato CM, Martins GA, High FA, DiCioccio CB, Reiner SL, Hunter CA. Cutting Edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter. J Immunol. 2004;173:1514\u20137.","journal-title":"J Immunol"},{"key":"3260_CR37","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/j.1600-065X.2010.00961.x","volume":"238","author":"A Balasubramani","year":"2010","unstructured":"Balasubramani A, Mukasa R, Hatton RD, Weaver CT. Regulation of the Ifng locus in the context of T-lineage specification and plasticity. Immunol Rev. 2010;238:216\u201332.","journal-title":"Immunol Rev"},{"key":"3260_CR38","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nri2487","volume":"9","author":"CB Wilson","year":"2009","unstructured":"Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol. 2009;9:91\u2013105.","journal-title":"Nat Rev Immunol"},{"key":"3260_CR39","first-page":"10.3791\/59275","volume":"144","author":"D Wang","year":"2019","unstructured":"Wang D, Starr R, Alizadeh D, Yang X, Forman SJ, Brown CE, et al. In Vitro tumor cell rechallenge for predictive evaluation of chimeric antigen receptor T cell antitumor function. J Visual Exper. 2019;144:10.3791\/59275.","journal-title":"J Visual Exper"},{"key":"3260_CR40","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ccell.2023.01.001","volume":"41","author":"X Liu","year":"2023","unstructured":"Liu X, Song J, Zhang H, Liu X, Zuo F, Zhao Y, et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer Cell. 2023;41:272\u201387.e9.","journal-title":"Cancer Cell"},{"key":"3260_CR41","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1016\/j.ymthe.2024.06.034","volume":"32","author":"Y Gong","year":"2024","unstructured":"Gong Y, Germeraad WTV, Zhang X, Wu N, Li B, Janssen L, et al. NKG2A genetic deletion promotes human primary NK cell anti-tumor responses better than an anti-NKG2A monoclonal antibody. Mol Ther. 2024;32:2711\u201327.","journal-title":"Mol Ther"},{"key":"3260_CR42","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.3389\/fimmu.2019.02590","volume":"10","author":"D Gotthardt","year":"2019","unstructured":"Gotthardt D, Trifinopoulos J, Sexl V, Putz EM. JAK\/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation. Front Immunol. 2019;10:2590.","journal-title":"Front Immunol"},{"key":"3260_CR43","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","volume":"8","author":"V Panwar","year":"2023","unstructured":"Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transd Target Ther. 2023;8:375.","journal-title":"Signal Transd Target Ther"},{"key":"3260_CR44","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.20892\/j.issn.2095-3941.2020.0791","volume":"18","author":"C Zhang","year":"2021","unstructured":"Zhang C, Yin J, Zheng J, Xiao J, Hu J, Su Y, et al. EZH2 identifies the precursors of human natural killer cells with trained immunity. Cancer Biol Med. 2021;18:1021\u201339.","journal-title":"Cancer Biol Med"},{"key":"3260_CR45","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.adk4893","volume":"9","author":"JA Foltz","year":"2024","unstructured":"Foltz JA, Tran J, Wong P, Fan C, Schmidt E, Fisk B, et al. Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation. Sci Immunol. 2024;9:eadk4893.","journal-title":"Sci Immunol"},{"key":"3260_CR46","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/s13045-022-01376-3","volume":"15","author":"S Caruso","year":"2022","unstructured":"Caruso S, De Angelis B, Del Bufalo F, Ciccone R, Donsante S, Volpe G, et al. Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia. J Hematol Oncol. 2022;15:163.","journal-title":"J Hematol Oncol"},{"key":"3260_CR47","doi-asserted-by":"crossref","DOI":"10.1002\/cpz1.864","volume":"3","author":"Y Nouri","year":"2023","unstructured":"Nouri Y, Weinkove R, Perret R. An In Vitro Model to Assess CRS Potential of CAR T Cells Using a Tumor Cell Line and Autologous Monocytes. Curr Protoc. 2023;3:e864.","journal-title":"Curr Protoc"},{"key":"3260_CR48","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00262-023-03586-1","volume":"73","author":"X Chen","year":"2024","unstructured":"Chen X, Tan B, Xing H, Zhao X, Ping Y, Zhang Z, et al. Allogeneic CAR-T cells with of HLA-A\/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies. Cancer Immunol Immunother CII. 2024;73:13.","journal-title":"Cancer Immunol Immunother CII"},{"key":"3260_CR49","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s40164-025-00633-8","volume":"14","author":"LV J\u00f8rgensen","year":"2025","unstructured":"J\u00f8rgensen LV, Christensen EB, Barnkob MB, Barington T. The clinical landscape of CAR NK cells. Exp Hematol Oncol. 2025;14:46.","journal-title":"Exp Hematol Oncol"},{"key":"3260_CR50","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2024.112156","volume":"133","author":"S Vahidi","year":"2024","unstructured":"Vahidi S, Zabeti Touchaei A, Samadani AA. IL-15 as a key regulator in NK cell-mediated immunotherapy for cancer: From bench to bedside. Int Immunopharmacol. 2024;133:112156.","journal-title":"Int Immunopharmacol"},{"key":"3260_CR51","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-51287-6","volume":"9","author":"EO Ojo","year":"2019","unstructured":"Ojo EO, Sharma AA, Liu R, Moreton S, Checkley-Luttge MA, Gupta K, et al. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Sci Rep. 2019;9:14916.","journal-title":"Sci Rep"},{"key":"3260_CR52","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s12026-017-8982-3","volume":"66","author":"R Sharma","year":"2018","unstructured":"Sharma R, Das A. IL-2 mediates NK cell proliferation but not hyperactivity. Immunol Res. 2018;66:151\u20137.","journal-title":"Immunol Res"},{"key":"3260_CR53","doi-asserted-by":"crossref","first-page":"930","DOI":"10.3389\/fimmu.2017.00930","volume":"8","author":"Y Wu","year":"2017","unstructured":"Wu Y, Tian Z, Wei H. Developmental and Functional Control of Natural Killer Cells by Cytokines. Front Immunol. 2017;8:930.","journal-title":"Front Immunol"},{"key":"3260_CR54","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3892\/mmr.2024.13171","volume":"29","author":"D Sun","year":"2024","unstructured":"Sun D, Shi X, Li S, Wang X, Yang X, Wan M,et al. CAR\u2011T cell therapy: A breakthrough in traditional cancer treatment strategies (Review). Mol Med Rep. 2024;29:47.","journal-title":"Mol Med Rep"},{"key":"3260_CR55","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00262-024-03765-8","volume":"73","author":"N Shrestha","year":"2024","unstructured":"Shrestha N, Dee MJ, Chaturvedi P, Leclerc GM, Mathyer M, Dufour C, et al. A \u201cPrime and Expand\u201d strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy. Cancer Immunol Immunother CII. 2024;73:179.","journal-title":"Cancer Immunol Immunother CII"},{"key":"3260_CR56","volume":"15","author":"JL Oyer","year":"2024","unstructured":"Oyer JL, Croom-Perez TJ, Hasan MF, Rivera-Huertas JA, Gitto SB, Mucha JM, et al. PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival. Front Immunol. 2024;15:1383281.","journal-title":"Front Immunol"},{"key":"3260_CR57","doi-asserted-by":"crossref","first-page":"357ra123","DOI":"10.1126\/scitranslmed.aaf2341","volume":"8","author":"R Romee","year":"2016","unstructured":"Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 2016;8:357ra123.","journal-title":"Sci Transl Med"},{"key":"3260_CR58","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-11-230","volume":"11","author":"C Rohde","year":"2010","unstructured":"Rohde C, Zhang Y, Reinhardt R, Jeltsch A. BISMA-fast and accurate bisulfite sequencing data analysis of individual clones from unique and repetitive sequences. BMC Bioinf. 2010;11:230.","journal-title":"BMC Bioinf"}],"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03260-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03260-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03260-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:38:43Z","timestamp":1792125523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-026-03260-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3260"],"URL":"https:\/\/doi.org\/10.1038\/s41420-026-03260-2","relation":{},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"17 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The studies involving human peripheral blood and PBMC cells from healthy volunteers were approved by Shanghai Hycells Biotechnology Co., Ltd (Ethics Approval Number: HYS-LQ-001 and EC-SMP-2024017). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was required from the participants. All animal experiments were conducted in compliance with the guiding principles approved by the Ethical Committee for Animal Care and Use of the East China Normal University (Ethics Approval Number: AR2025-150).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All authors consent to publication.","order":3,"name":"Ethics","label":"Consent to publication","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"417"}}