{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:37:35Z","timestamp":1789097855859,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101929"],"award-info":[{"award-number":["82101929"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Proliferation"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Natural Killer (NK) cells have shown promising prospects in \u2018off\u2010the\u2010shelf\u2019 cell therapy, particularly the NK\u201092 cell line, which can serve as a foundation for the next generation of universal chimeric antigen receptor (CAR)\u2010engineered NK products. A key strategy for generating universal cellular products is the elimination of the beta\u20102\u2010microglobulin (B2M) gene, which encodes a component of MHC class I molecules (MHC\u2010I) that plays a role in the presentation of foreign antigens and in the \u2018licensing\u2019 or \u2018education\u2019 of NK cells. To functionally study the impacts of MHC\u2010I deficiency on NK\u201092, we generated a B2M knockout (KO) NK\u201092MI (B\u201092) cell line and compared the multidimensional properties of B2M KO and wild\u2010type NK\u201092MI cells in terms of biological phenotypes, effector functions, and transcriptomic signatures. We observed a decrease in activating receptors, cytokine production, and cytotoxicity in B\u201092 cells. Further analysis of signalling events revealed that the upregulated expression and phosphorylation of SHP\u20101 in B\u201092 cells inhibited the phosphorylation levels of STAT3 and ERK, thereby affecting their killing function. By knocking out SHP\u20101 (PTPN6), we partially restored the cytotoxic function of B\u201092 cells. Notably, we also found that CAR modification can overcome the hyporesponsiveness of B\u201092 cells. These findings will facilitate further exploration in the development of NK cell\u2010based products.<\/jats:p>","DOI":"10.1111\/cpr.70035","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T08:00:57Z","timestamp":1743580857000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting <scp>SHP<\/scp>\u20101\u2010Mediated Inhibition of <scp>STAT3<\/scp> and <scp>ERK<\/scp> Signalling Pathways Rescues the Hyporesponsiveness of <scp>MHC<\/scp>\u2010I\u2010Deficient <scp>NK<\/scp>\u2010<scp>92MI<\/scp>"],"prefix":"10.1111","volume":"58","author":[{"given":"Kuo","family":"Yu","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin 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(Heilongjiang) Co., Ltd  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Sun","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Obstetrical Department First Affiliated Hospital, Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Xu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Pathology First Affiliated Hospital, Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqiu","family":"Teng","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song Guo","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Immunology School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiren","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin China"},{"name":"Department of Cardiology and Pharmacy and Breast Cancer Surgery Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorder and Cancer Related Cardiovascular Diseases  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenkun","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Cell Transplantation Harbin Medical University  Harbin China"},{"name":"Central Laboratory First Affiliated Hospital, Harbin Medical University  Harbin China"},{"name":"Department of Hematology First Affiliated Hospital of Harbin Medical University, the Institute of the Hematology and Oncology of Heilongjiang Province  Harbin China"},{"name":"The Somatic Cells Bioengineering Technology Research Center of Qinhuangdao  Qinhuangdao 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