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Conventional bispecific T cell engagers, typically constructed from aggregation-prone single-chain variable fragments (scFvs), suffer from structural instability and an antigenic scope restricted to extracellular targets. To overcome these critical limitations, we presented a proof-of-concept study establishing a modular bispecific VHH\u2011VHH immunotherapeutic platform. Specifically, we developed a first-in-class TCR-mimic bispecific nanobody (Nb)-based T cell engager (TCRm Bi-NbTE) platform that simultaneously engages CD3\u03b5 on T cells and tumor-specific peptide-MHC class I (pMHC I) complexes, exemplified by HLA-A2\/WT1\n                    <jats:sub>126-134<\/jats:sub>\n                    or HLA-A2\/GPC3\n                    <jats:sub>144-152<\/jats:sub>\n                    . Functional analyses in vitro and in vivo studies demonstrated that TCRm Bi-NbTE exhibits exceptional specificity, potently induces antigen-restricted T cell activation, and mediates selective lysis of pMHC I\u207a tumor cells while sparing antigen-negative cells. In multiple mouse xenograft models, including both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models, TCRm Bi-NbTE significantly suppressed tumor growth, prolonged survival, and enhanced T cell infiltration without treatment-related adverse effects. By redirecting T cell against intracellular antigens in an HLA-restricted manner, TCRm Bi-NbTE establishes a modular, scalable, and clinically translatable platform for next-generation cancer immunotherapy across a broad spectrum of solid and hematologic malignancies.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02745-x","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T23:02:51Z","timestamp":1782342171000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TCR-mimic bispecific nanobody-based T cell engager targeting intracellular tumor antigens for cancer immunotherapy"],"prefix":"10.1038","volume":"11","author":[{"given":"Ziqiang","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiong","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenxia","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiqun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9049-2077","authenticated-orcid":false,"given":"Xiaoling","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"2745_CR1","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1038\/s43018-023-00586-z","volume":"4","author":"RC Bargou","year":"2023","unstructured":"Bargou, R. 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