{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:52:57Z","timestamp":1785372777521,"version":"3.55.0"},"reference-count":10,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"unspecified","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"crossref","award":["DOD W81XWH2110841"],"award-info":[{"award-number":["DOD W81XWH2110841"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,5,6]]},"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:p>Chimeric antigen receptor (CAR) therapies have revolutionized cancer treatment by enabling immune cells to target tumor cells with high specificity. While extensive research has focused on optimizing single-chain variable fragment (scFv) affinity in CAR-T cells, its impact on CAR-natural killer (NK) cell function remains less understood. A recent study by Rahnama <jats:italic>et al<\/jats:italic>, published in the <jats:italic>Journal for ImmunoTherapy of Cancer<\/jats:italic>, addresses this gap by investigating how fine-tuning scFv affinity influences CAR-NK efficacy against acute myeloid leukemia. The study demonstrates that lower-affinity 7G3-based CAR-NK cells exhibit superior antigen discrimination, prolonged persistence, and enhanced tumor control compared with their high-affinity counterparts. However, findings with 26292-based CAR-NK cells reveal a more complex, context-dependent relationship between scFv affinity and cytotoxic function. These results highlight the need for individualized optimization of CAR designs, considering factors such as epitope accessibility, ligand-binding kinetics, and cellular context. Future studies incorporating real-time kinetic analyses and tumor microenvironment modeling will be crucial for refining CAR-NK therapies. Striking the right balance between binding affinity, dwell time, and serial killing capacity could enhance CAR-NK therapeutic potential while minimizing toxicity risks.<\/jats:p>","DOI":"10.1136\/jitc-2025-012139","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T02:45:27Z","timestamp":1747881927000},"page":"e012139","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["CAR-NK\u2019s balancing act: when scFv affinity is not too tight, not too loose\u2026 but just right?"],"prefix":"10.1136","volume":"13","author":[{"given":"Yanling","family":"Liao","sequence":"first","affiliation":[{"name":"Pediatrics, New York Medical College, Valhalla, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2075-434X","authenticated-orcid":false,"given":"Mitchell S","family":"Cairo","sequence":"additional","affiliation":[{"name":"Pediatrics, New York Medical College, Valhalla, New York, USA"},{"name":"Pediatrics, Medicine, Cell Biology and Anatomy, Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"2025100311344042000_13.5.e012139.1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1032403"},{"key":"2025100311344042000_13.5.e012139.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0549-5"},{"key":"2025100311344042000_13.5.e012139.3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.00917"},{"key":"2025100311344042000_13.5.e012139.4","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-010763","article-title":"Single-chain variable fragment affinity tuning can optimize anti-AML CAR-NK cell functionality","volume":"13","author":"Rahnama","year":"2025","journal-title":"J Immunother Cancer"},{"key":"2025100311344042000_13.5.e012139.5","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0114"},{"key":"2025100311344042000_13.5.e012139.6","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-009726","article-title":"Circumventing resistance within the Ewing sarcoma microenvironment by combinatorial innate immunotherapy","volume":"12","author":"Luo","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2025100311344042000_13.5.e012139.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910607"},{"key":"2025100311344042000_13.5.e012139.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02785-8"},{"key":"2025100311344042000_13.5.e012139.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.04.017"},{"key":"2025100311344042000_13.5.e012139.10","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e318053ed8e"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-012139","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T18:34:50Z","timestamp":1759516490000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-012139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":10,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,21]]},"published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1136\/jitc-2025-012139"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-012139","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5]]}}}