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Although artificial intelligence (AI) has explosively accelerated de novo protein design, the challenge of therapeutic TCR design has been overlooked by most researchers. Existing TCR engineering relies heavily on isolating antigen-specific TCRs from tumor tissues, which requires a large amount of labor resources and wet experimental verification. To mitigate this issue, we present TCRdesign, a pretrained generative protein language model (PLM) for the de novo design of artificial TCR $\\beta $-chain complementarity-determining region 3 sequences conditioned on antigen-binding specificity (BS). In parallel, we develop a high-accuracy binding predictor (TCRBinder) that couples paired $\\alpha $\/$\\beta $ chain information with antigen sequences to assess BS. Our in silico comparisons demonstrate that (i) TCRdesign surpasses state-of-the-art baselines in generating antigen-specific TCR sequences. The model leverages paired-chain coherence to refine amino-acid level interaction patterns. (ii) TCRdesign-generated TCR sequences exhibit better antigen binding capability to diverse oncogenic hotspots compared with natural counterparts. (iii) TCRdesign inherits the intrinsic properties of large PLMs, enabling effectively identify the determinant residues in TCR-antigen binding, which enhances its interpretability. These results highlight the significant capability of TCRdesign in understanding and generating TCR sequences with an antigen-specific interaction pattern, charting a versatile path toward AI-driven T-cell engineering for precision immunotherapy.<\/jats:p>","DOI":"10.1093\/bib\/bbaf691","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T12:34:31Z","timestamp":1765197271000},"source":"Crossref","is-referenced-by-count":7,"title":["TCRdesign: an antigen-specific generative language model for\n                    <i>de novo<\/i>\n                    design of T-cell receptors"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6645-6890","authenticated-orcid":false,"given":"Xiaokun","family":"Li","sequence":"first","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology , West Dazhi Street, 150001 Harbin ,","place":["China"]},{"name":"School of Computer Science and Technology, Heilongjiang University , Xuefu Road, 150080 Harbin ,","place":["China"]},{"name":"Postdoctoral Program of Heilongjiang Hengxun Technology Co., Ltd. , Xuefu Road, 150080 Harbin ,","place":["China"]},{"name":"Shandong Hengxun Technology Co., Ltd. , Miaoling Road, 266100 Qingdao ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6524-9443","authenticated-orcid":false,"given":"Qiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology , West Dazhi Street, 150001 Harbin ,","place":["China"]},{"name":"Zhengzhou Research Institute, Harbin Institute of Technology , 450000 Zhengzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4952-9178","authenticated-orcid":false,"given":"Long","family":"Xu","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology , West Dazhi Street, 150001 Harbin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8022-9793","authenticated-orcid":false,"given":"Weihe","family":"Dong","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology , West Dazhi Street, 150001 Harbin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1347-3491","authenticated-orcid":false,"given":"Kuanquan","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology , West Dazhi Street, 150001 Harbin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-8782","authenticated-orcid":false,"given":"Suyu","family":"Dong","sequence":"additional","affiliation":[{"name":"Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST) , Suite 4328, Thuwal 23955-6900 ,","place":["Kingdom of Saudi Arabia"]},{"name":"Center of Excellence for Smart Health (KCSH), King Abdullah University of Science and Technology (KAUST) , Suite 4328, Thuwal 23955-6900 ,","place":["Kingdom of Saudi Arabia"]},{"name":"Center of Excellence on Generative AI, King Abdullah University of Science and Technology (KAUST) , Suite 4328, Thuwal 23955-6900 ,","place":["Kingdom of Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology, Harbin Institute of Technology (Shenzhen) , Xili University Town, 518055 Shenzhen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3662-0335","authenticated-orcid":false,"given":"Gongning","family":"Luo","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology , West Dazhi Street, 150001 Harbin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9738-2361","authenticated-orcid":false,"given":"Xianyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Harbin Medical University Cancer Hospital , Haping Road, 150081 Harbin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4008-702X","authenticated-orcid":false,"given":"Tiansong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, and Traditional Chinese Medicine Informatics Key Laboratory of Heilongjiang Province , Heping Road, 150040 Harbin ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7108-3574","authenticated-orcid":false,"given":"Xin","family":"Gao","sequence":"additional","affiliation":[{"name":"Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST) , Suite 4328, Thuwal 23955-6900 ,","place":["Kingdom of Saudi Arabia"]},{"name":"Center of Excellence for Smart Health (KCSH), King Abdullah University of Science and Technology (KAUST) , Suite 4328, Thuwal 23955-6900 ,","place":["Kingdom of Saudi Arabia"]},{"name":"Center of Excellence on Generative AI, King Abdullah University of Science and Technology (KAUST) , Suite 4328, Thuwal 23955-6900 ,","place":["Kingdom of Saudi 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