{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:47:52Z","timestamp":1793998072009,"version":"4.8.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"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":["82300252"],"award-info":[{"award-number":["82300252"]}],"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":["82170163"],"award-info":[{"award-number":["82170163"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A1515110828"],"award-info":[{"award-number":["2022A1515110828"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2022M721498"],"award-info":[{"award-number":["2022M721498"]}],"id":[{"id":"10.13039\/501100002858","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:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>NK cells engineered to express interleukin-15 (IL-15) and a CD19-targeted chimeric antigen receptor (CAR) have been used to treat patients with relapsed and\/or refractory B cell malignances, demonstrating encouraging outcomes and favorable safety profile. However, the effect of IL-21 in CAR-NK cell therapy remains unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>CD19-specific CAR with 4-1BB costimulatory domain and cytokine IL-21 or IL-15 was constructed and transduced into peripheral blood (PB)-derived NK cells to produce CD19-CAR-IL21 NK cells (CAR-21) or CD19-CAR-IL15 NK cells (CAR-15), respectively. The phenotypic profile, transcriptomic characteristics, functionality and anti-tumor activity of CAR-21 NK cells and CAR-15 NK cells were compared.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Compared with CAR-NK cells co-expressing IL-15, CAR-NK cells co-expressing IL-21 exhibited significantly increased IFN-\u03b3, TNF-\u03b1 and Granzyme B production, as well as degranulation, in response to CD19<jats:sup>+<\/jats:sup> Raji lymphoma cells, resulting in enhanced cytotoxic activity upon repetitive tumor stimulation. Furthermore, IL-21 co-expression improved the in vivo persistence of CAR-NK cells and significantly suppressed tumor growth in a xenograft Raji lymphoma murine model, leading to prolonged survival of CD19<jats:sup>+<\/jats:sup> tumor-bearing mice. RNA sequencing revealed that CAR-21 NK cells have a distinct transcriptomic signature characterized by enriched in cytokine, cytotoxicity, and metabolic related signaling, when compared with CAR-15 NK or CAR NK cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study demonstrated that CD19-specific CAR-NK cells engineered to express IL-21 exhibit superior persistence and anti-tumor activity against CD19<jats:sup>+<\/jats:sup> tumor compared to CAR-NK cells co-expressing IL-15, which might be a promising therapeutic strategy for treating patients with relapse or refractory B cell malignances.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s40164-025-00639-2","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:22:01Z","timestamp":1743726121000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Interleukin-21 engineering enhances CD19-specific CAR-NK cell activity against B-cell lymphoma via enriched metabolic pathways"],"prefix":"10.1186","volume":"14","author":[{"given":"Bailin","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqiu","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiusui","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikai","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihong","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsheng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qifa","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"issue":"1","key":"639_CR1","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1056\/NEJMra1706169","volume":"379","author":"CH June","year":"2018","unstructured":"June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64\u201373.","journal-title":"N Engl J Med"},{"issue":"7949","key":"639_CR2","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/s41586-023-05707-3","volume":"614","author":"L Labanieh","year":"2023","unstructured":"Labanieh L, Mackall CL. CAR immune cells: design principles, resistance and the next generation. Nature. 2023;614(7949):635\u201348.","journal-title":"Nature"},{"issue":"1","key":"639_CR3","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13045-020-00953-8","volume":"13","author":"R Gu","year":"2020","unstructured":"Gu R, Liu F, Zou D, Xu Y, Lu Y, Liu B, et al. Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia. J Hematol Oncol. 2020;13(1):122.","journal-title":"J Hematol Oncol"},{"issue":"1","key":"639_CR4","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s13045-023-01492-8","volume":"16","author":"P Zhang","year":"2023","unstructured":"Zhang P, Zhang G, Wan X. Challenges and new technologies in adoptive cell therapy. J Hematol Oncol. 2023;16(1):97.","journal-title":"J Hematol Oncol"},{"issue":"10","key":"639_CR5","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/s41568-022-00491-0","volume":"22","author":"TJ Laskowski","year":"2022","unstructured":"Laskowski TJ, Biederst\u00e4dt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022;22(10):557\u201375.","journal-title":"Nat Rev Cancer"},{"key":"639_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217264","volume":"605","author":"Y Wang","year":"2024","unstructured":"Wang Y, Chang YJ, Chen J, Han M, Hu J, Hu J, et al. Consensus on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation in China: 2024 update. Cancer Lett. 2024;605: 217264.","journal-title":"Cancer Lett"},{"issue":"1","key":"639_CR7","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s40164-023-00431-0","volume":"12","author":"Y Zhang","year":"2023","unstructured":"Zhang Y, Zhou W, Yang J, Yang J, Wang W. Chimeric antigen receptor engineered natural killer cells for cancer therapy. Exp Hematol Oncol. 2023;12(1):70.","journal-title":"Exp Hematol Oncol"},{"issue":"3","key":"639_CR8","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1038\/s41591-023-02785-8","volume":"30","author":"D Marin","year":"2024","unstructured":"Marin D, Li Y, Basar R, Rafei H, Daher M, Dou J, et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19(+) B cell tumors: a phase 1\/2 trial. Nat Med. 2024;30(3):772\u201384.","journal-title":"Nat Med"},{"issue":"6","key":"639_CR9","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1056\/NEJMoa1910607","volume":"382","author":"E Liu","year":"2020","unstructured":"Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545\u201353.","journal-title":"N Engl J Med"},{"issue":"1","key":"639_CR10","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":"3","key":"639_CR11","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/1074-7613(95)90047-0","volume":"2","author":"X Cao","year":"1995","unstructured":"Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995;2(3):223\u201338.","journal-title":"Immunity"},{"issue":"4","key":"639_CR12","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1016\/j.immuni.2019.03.028","volume":"50","author":"WJ Leonard","year":"2019","unstructured":"Leonard WJ, Lin JX, O\u2019Shea JJ. The \u03b3(c) family of cytokines: basic biology to therapeutic ramifications. Immunity. 2019;50(4):832\u201350.","journal-title":"Immunity"},{"issue":"2\u20133","key":"639_CR13","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0162-3109(97)00041-6","volume":"37","author":"R Baluna","year":"1997","unstructured":"Baluna R, Vitetta ES. Vascular leak syndrome: a side effect of immunotherapy. Immunopharmacology. 1997;37(2\u20133):117\u201332.","journal-title":"Immunopharmacology"},{"key":"639_CR14","doi-asserted-by":"publisher","first-page":"2269","DOI":"10.2147\/DDDT.S308578","volume":"15","author":"Y Qiu","year":"2021","unstructured":"Qiu Y, Su M, Liu L, Tang Y, Pan Y, Sun J. Clinical application of cytokines in cancer immunotherapy. Drug Des Devel Ther. 2021;15:2269\u201387.","journal-title":"Drug Des Devel Ther"},{"issue":"12","key":"639_CR15","doi-asserted-by":"publisher","first-page":"a028472","DOI":"10.1101\/cshperspect.a028472","volume":"10","author":"TA Waldmann","year":"2018","unstructured":"Waldmann TA. Cytokines in cancer immunotherapy. Cold Spring Harb Perspect Biol. 2018;10(12):a028472.","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"8","key":"639_CR16","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1182\/blood.2021011532","volume":"139","author":"MM Berrien-Elliott","year":"2022","unstructured":"Berrien-Elliott MM, Becker-Hapak M, Cashen AF, Jacobs M, Wong P, Foster M, et al. Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy. Blood. 2022;139(8):1177\u201383.","journal-title":"Blood"},{"issue":"23","key":"639_CR17","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.1182\/blood-2017-12-823757","volume":"131","author":"R Romee","year":"2018","unstructured":"Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018;131(23):2515\u201327.","journal-title":"Blood"},{"issue":"1","key":"639_CR18","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s13045-025-01669-3","volume":"18","author":"RM Shapiro","year":"2025","unstructured":"Shapiro RM, Sheffer M, Booker MA, Tolstorukov MY, Birch GC, Sade-Feldman M, et al. First-in-human evaluation of memory-like NK cells with an IL-15 super-agonist and CTLA-4 blockade in advanced head and neck cancer. J Hematol Oncol. 2025;18(1):17.","journal-title":"J Hematol Oncol"},{"issue":"6808","key":"639_CR19","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(6808):57\u201363.","journal-title":"Nature"},{"issue":"11","key":"639_CR20","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1158\/2326-6066.CIR-23-0151","volume":"11","author":"C Zhang","year":"2023","unstructured":"Zhang C, Kadu S, Xiao Y, Johnson O, Kelly A, O\u2019Connor RS, et al. Sequential exposure to IL21 and IL15 during human natural killer cell expansion optimizes yield and function. Cancer Immunol Res. 2023;11(11):1524\u201337.","journal-title":"Cancer Immunol Res"},{"issue":"7","key":"639_CR21","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1002\/bit.28086","volume":"119","author":"M Chang","year":"2022","unstructured":"Chang M, Tang X, Nelson L, Nyberg G, Du Z. Differential effects on natural killer cell production by membrane-bound cytokine stimulations. Biotechnol Bioeng. 2022;119(7):1820\u201338.","journal-title":"Biotechnol Bioeng"},{"key":"639_CR22","doi-asserted-by":"publisher","first-page":"15776","DOI":"10.1038\/ncomms15776","volume":"8","author":"H Seo","year":"2017","unstructured":"Seo H, Jeon I, Kim BS, Park M, Bae EA, Song B, et al. IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours. Nat Commun. 2017;8:15776.","journal-title":"Nat Commun"},{"issue":"27","key":"639_CR23","doi-asserted-by":"publisher","first-page":"3396","DOI":"10.1200\/JCO.2011.40.0655","volume":"30","author":"TM Petrella","year":"2012","unstructured":"Petrella TM, Tozer R, Belanger K, Savage KJ, Wong R, Smylie M, et al. Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J Clin Oncol. 2012;30(27):3396\u2013401.","journal-title":"J Clin Oncol"},{"key":"639_CR24","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/2051-1426-2-2","volume":"2","author":"S Bhatia","year":"2014","unstructured":"Bhatia S, Curti B, Ernstoff MS, Gordon M, Heath EI, Miller WH Jr, et al. Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1\/2 study. J Immunother Cancer. 2014;2:2.","journal-title":"J Immunother Cancer"},{"issue":"8","key":"639_CR25","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1016\/j.ccell.2024.07.007","volume":"42","author":"M Shanley","year":"2024","unstructured":"Shanley M, Daher M, Dou J, Li S, Basar R, Rafei H, et al. Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD. Cancer Cell. 2024;42(8):1450-66.e11.","journal-title":"Cancer Cell"},{"key":"639_CR26","doi-asserted-by":"publisher","first-page":"1130442","DOI":"10.3389\/fimmu.2023.1130442","volume":"14","author":"B He","year":"2023","unstructured":"He B, Mai Q, Pang Y, Deng S, He Y, Xue R, et al. Cytokines induced memory-like NK cells engineered to express CD19 CAR exhibit enhanced responses against B cell malignancies. Front Immunol. 2023;14:1130442.","journal-title":"Front Immunol"},{"issue":"1","key":"639_CR27","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s40164-024-00553-z","volume":"13","author":"Q Mai","year":"2024","unstructured":"Mai Q, He B, Deng S, Zeng Q, Xu Y, Wang C, et al. Efficacy of NKG2D CAR-T cells with IL-15\/IL-15R\u03b1 signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder. Exp Hematol Oncol. 2024;13(1):85.","journal-title":"Exp Hematol Oncol"},{"issue":"5","key":"639_CR28","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1182\/blood.2020007748","volume":"137","author":"M Daher","year":"2021","unstructured":"Daher M, Basar R, Gokdemir E, Baran N, Uprety N, Nunez Cortes AK, et al. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood. 2021;137(5):624\u201336.","journal-title":"Blood"},{"issue":"1","key":"639_CR29","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13045-024-01525-w","volume":"17","author":"A Van den Eynde","year":"2024","unstructured":"Van den Eynde A, Gehrcken L, Verhezen T, Lau HW, Hermans C, Lambrechts H, et al. IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts. J Hematol Oncol. 2024;17(1):8.","journal-title":"J Hematol Oncol"},{"issue":"1","key":"639_CR30","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/s40164-023-00461-8","volume":"12","author":"Q Ren","year":"2023","unstructured":"Ren Q, Zu Y, Su H, Lu Q, Xiang B, Luo Y, et al. Single VHH-directed BCMA CAR-NK cells for multiple myeloma. Exp Hematol Oncol. 2023;12(1):98.","journal-title":"Exp Hematol Oncol"},{"issue":"6","key":"639_CR31","doi-asserted-by":"publisher","DOI":"10.4161\/onci.24522","volume":"2","author":"SJ Santegoets","year":"2013","unstructured":"Santegoets SJ, Turksma AW, Powell DJ Jr, Hooijberg E, de Gruijl TD. IL-21 in cancer immunotherapy: at the right place at the right time. Oncoimmunology. 2013;2(6): e24522.","journal-title":"Oncoimmunology"},{"issue":"1","key":"639_CR32","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41392-024-01792-6","volume":"9","author":"W Zhu","year":"2024","unstructured":"Zhu W, Zhang Z, Chen J, Chen X, Huang L, Zhang X, et al. A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma. Signal Transduct Target Ther. 2024;9(1):101.","journal-title":"Signal Transduct Target Ther"},{"issue":"10","key":"639_CR33","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.it.2022.08.004","volume":"43","author":"S Ma","year":"2022","unstructured":"Ma S, Caligiuri MA, Yu J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol. 2022;43(10):833\u201347.","journal-title":"Trends Immunol"},{"issue":"1","key":"639_CR34","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41467-024-44789-z","volume":"15","author":"I Dean","year":"2024","unstructured":"Dean I, Lee CYC, Tuong ZK, Li Z, Tibbitt CA, Willis C, et al. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat Commun. 2024;15(1):683.","journal-title":"Nat Commun"},{"issue":"1","key":"639_CR35","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1186\/s12967-022-03626-x","volume":"20","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Zhuang Q, Wang F, Zhang C, Xu C, Gu A, et al. Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy. J Transl Med. 2022;20(1):432.","journal-title":"J Transl Med"},{"issue":"10","key":"639_CR36","doi-asserted-by":"publisher","first-page":"3907","DOI":"10.1158\/0008-5472.CAN-07-6842","volume":"68","author":"C Badoual","year":"2008","unstructured":"Badoual C, Bouchaud G, Agueznay Nel H, Mortier E, Hans S, Gey A, et al. The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res. 2008;68(10):3907\u201314.","journal-title":"Cancer Res"},{"issue":"1","key":"639_CR37","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1182\/blood.V92.1.252.413k08_252_258","volume":"92","author":"U D\u00f6bbeling","year":"1998","unstructured":"D\u00f6bbeling U, Dummer R, Laine E, Potoczna N, Qin JZ, Burg G. Interleukin-15 is an autocrine\/paracrine viability factor for cutaneous T-cell lymphoma cells. Blood. 1998;92(1):252\u20138.","journal-title":"Blood"},{"key":"639_CR38","doi-asserted-by":"publisher","first-page":"1090311","DOI":"10.3389\/fimmu.2023.1090311","volume":"14","author":"Y Zhou","year":"2023","unstructured":"Zhou Y, Quan G, Liu Y, Shi N, Wu Y, Zhang R, et al. The application of Interleukin-2 family cytokines in tumor immunotherapy research. Front Immunol. 2023;14:1090311.","journal-title":"Front Immunol"},{"issue":"1","key":"639_CR39","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41392-024-01915-z","volume":"9","author":"RC Schelker","year":"2024","unstructured":"Schelker RC, Fioravanti J, Mastrogiovanni F, Baldwin JG, Rana N, Li P, et al. LIM-domain-only 4 (LMO4) enhances CD8(+) T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling. Signal Transduct Target Ther. 2024;9(1):199.","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"639_CR40","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 CARCD123-NK cells for the treatment of acute myeloid leukaemia. J Hematol Oncol. 2022;15(1):163.","journal-title":"J Hematol Oncol"},{"issue":"1","key":"639_CR41","doi-asserted-by":"publisher","first-page":"108597","DOI":"10.1016\/j.isci.2023.108597","volume":"27","author":"Y Liu","year":"2024","unstructured":"Liu Y, Dang Y, Zhang C, Liu L, Cai W, Li L, et al. IL-21-armored B7H3 CAR-iNKT cells exert potent antitumor effects. iScience. 2024;27(1):108597.","journal-title":"iScience."}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00639-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-025-00639-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00639-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T14:01:25Z","timestamp":1743775285000},"score":1,"resource":{"primary":{"URL":"https:\/\/ehoonline.biomedcentral.com\/articles\/10.1186\/s40164-025-00639-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,2]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["639"],"URL":"https:\/\/doi.org\/10.1186\/s40164-025-00639-2","relation":{},"ISSN":["2162-3619"],"issn-type":[{"value":"2162-3619","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,2]]},"assertion":[{"value":"1 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 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":"The study received approval from the Ethics Committee of Southern Medical University (No. SMUL2023080) and the Guangzhou Blood Center (No. GZBC2022068). All animal studies were approved by the Institutional Animal Care and Use Committee of Southern Medical University. The authors have received permission to publish the research data from all the participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors declare no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"51"}}