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However, their efficacy is often limited by immune\u2010evasion, especially major histocompatibility complex I (MHC\u2010I)\u2010mediated NK cell inhibition. NK cell engagers (NKCEs) can redirect NK cells to tumor for more effective immunotherapy, but most current NKCEs target tumor\u2010associated antigens (TAAs), risking on\u2010target, off\u2010tumor toxicity in clinical applications. Neoantigens, as tumor\u2010specific antigens (TSAs) arising from somatic mutations and presented by MHC\u2010I on tumor cell surfaces, represent ideal tumor\u2010specific target. Here, we engineered NKCEs built on neoantigen\u2010targeting TCR\u2010mimic antibodies (TCRm\u2010Abs) to enhance tumor\u2010specific NK cell\u2010mediated cytotoxicity. Using a high\u2010throughput hydrogel\u2010based microwell single\u2010cell chip (HMSC\u2010chip) coupled with T2 cell\u2010based de\u2010selection, we identified C33\u2010Ab, a functional TCRm\u2010Ab specific for p53\n                    <jats:sup>R175H<\/jats:sup>\n                    \/HLA\u2010A*02:01, from \u223c500,000 hybridoma cells within 8 weeks. Based on this TCRm\u2010Ab, we constructed a bispecific NKCE (C33\u00d7CD16), a single\u2010chain diabody (scDb) linking C33\u2010Ab to an anti\u2010CD16 scFv. C33\u00d7CD16 specifically bridges NK cells with p53\n                    <jats:sup>R175H<\/jats:sup>\n                    \/HLA\u2010A*02:01\u2010positive cancer cells. It potently enhanced NK cell\u2010mediated cytotoxicity in vitro and antitumor efficacy in vivo upon adoptive NK\u2010cell transfer. This TCRm\u2010Ab\u2010based bispecific NKCE offers a promising strategy for tumor\u2010specific NK cell\u2010mediated immunotherapy by targeting intracellular oncogenic hotspot mutations.\n                  <\/jats:p>","DOI":"10.1002\/mco2.71058","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:31:53Z","timestamp":1792049513000},"source":"Crossref","is-referenced-by-count":0,"title":["Bispecific NK\u2010Cell Engager Targeting TP53 Mutation Through Integration of a TCR\u2010mimic Antibody"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7098-2790","authenticated-orcid":false,"given":"Hanfei","family":"Wu","sequence":"first","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"},{"name":"Department of Pharmaceutical Engineering School of Engineering China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Vaccine Clinical Evaluation Jiangsu Provincial Center for Disease Prevention and Control  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdie","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Ge","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyue","family":"Zhi","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobin","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanqian","family":"Yi","sequence":"additional","affiliation":[{"name":"School of Nano\u2010Tech and Nano\u2010Bionics University of Science and Technology of China  Hefei Anhui China"},{"name":"CAS Key Laboratory of Nano\u2010Bio Interface Suzhou Institute of Nano\u2010Tech and Nano\u2010Bionics Chinese Academy of Sciences  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Qiao","sequence":"additional","affiliation":[{"name":"Nanjing LivingChip Biotechnology Co., Ltd  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjun","family":"Cao","sequence":"additional","affiliation":[{"name":"Nanjing LivingChip Biotechnology Co., Ltd  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Mei","sequence":"additional","affiliation":[{"name":"Nanjing LivingChip Biotechnology Co., Ltd  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiping","family":"Jiao","sequence":"additional","affiliation":[{"name":"Clinical Research Ward The Sixth People's Hospital Shanghai Jiao Tong University  Shanghai China"},{"name":"TCRX Therapeutics (KeShiHua) Co. 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