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Adv."],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:p>T cell receptor (TCR)\u2013based immunotherapy is limited by tumor antigen heterogeneity, which frequently leads to relapse. We developed a bispecific TCR-JANUS engager that functions synergistically with TCR engineered T cells (TCR-T). In contrast to conventional T cell engagers targeting CD3, TCR-JANUS engages both the variable region of a transgenic TCR (TRBV) and a tumor surface antigen. Using a model system targeting a humanized KRAS-G12V\u2013specific TCR and trophoblast cell surface antigen 2 (Trop2), we show that TCR-JANUS effectively redirects TCR-T cells to lyse Trop2-expressing tumor cells while preserving intrinsic specificity toward the cognate pHLA target, thereby enabling simultaneous dual-antigen recognition. In heterogeneous tumor models, the combination of TCR-JANUS with TCR-T cells, an integrated system termed T Cell Dual Arsenal Recon, potently suppressed tumor growth by clearing antigenically divergent populations. Moreover, TCR-JANUS maintained enhanced T cell functionality with reduced exhaustion compared to anti-CD3\u2013based engagers upon chronic stimulation. Together, this approach offers a targeted and durable strategy to overcome antigenic heterogeneity, expanding the clinical prospects of TCR-T cell therapy for solid tumors.<\/jats:p>","DOI":"10.1126\/sciadv.aed9825","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:58:47Z","timestamp":1788976727000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["TCR-JANUS engager proteins enable bispecific targeting to overcome tumor heterogeneity in TCR-T cell therapy"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7674-272X","authenticated-orcid":true,"given":"Chenxi","family":"Cheng","sequence":"first","affiliation":[{"name":"Innovative Vaccine and Immunotherapy Research Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."},{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6227-3394","authenticated-orcid":true,"given":"Ting","family":"Liang","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1110-9313","authenticated-orcid":true,"given":"Pengju","family":"Yao","sequence":"additional","affiliation":[{"name":"Innovative Vaccine and Immunotherapy Research Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9449-3527","authenticated-orcid":true,"given":"Wenling","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5433-5539","authenticated-orcid":true,"given":"Huxuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2950-6032","authenticated-orcid":true,"given":"Xiaowen","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tian","sequence":"additional","affiliation":[{"name":"Innovative Vaccine and Immunotherapy Research Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."},{"name":"The School of Laboratory Medicine &amp; Life Sciences, Key Laboratory of Laboratory Medicine, Wenzhou Medical University, Ministry of Education of China, Wenzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Innovative Vaccine and Immunotherapy Research Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5434-7754","authenticated-orcid":true,"given":"Ni","family":"Yan","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danli","family":"Xie","sequence":"additional","affiliation":[{"name":"The School of Laboratory Medicine &amp; Life Sciences, Key Laboratory of Laboratory Medicine, Wenzhou Medical University, Ministry of Education of China, Wenzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5793-1023","authenticated-orcid":true,"given":"Fuming","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2599-4959","authenticated-orcid":true,"given":"Shuguang","family":"Tan","sequence":"additional","affiliation":[{"name":"Innovative Vaccine and Immunotherapy Research Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","first-page":"4004","article-title":"T cell receptor-based immunotherapy: A review","volume":"39","author":"Gao G. 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