{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:56:52Z","timestamp":1791205012602,"version":"4.1.0"},"reference-count":113,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3404000"],"award-info":[{"award-number":["2023YFC3404000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Soluble T-cell receptor (TCR)-based biologics (protein-based) are an emerging class of immunotherapeutic agents that recognize antigenic peptides presented by the human leukocyte antigen (HLA) on the surface of target cells. Furthermore, they simultaneously bind to cluster of differentiation 3 (CD3) subunits on T cells, recruit T cells to target cells, and promote T-cell activation and degranulation, ultimately eliminating tumor cells. Soluble TCR-based protein biologics target intracellular antigens that are inaccessible to conventional antibody-based drugs. Consequently, the development of soluble TCR-based protein biologics has generated significant interest. One soluble TCR-based protein biologic is already approved for marketing, and several other drugs are entering clinical stages. Soluble TCR-based protein biologics have substantial therapeutic benefits but may cause cytokine release syndrome (CRS), off-target toxicity, and drug resistance. This review outlines the structural characteristics and mechanisms of action of soluble TCR-based protein biologics, introduces nonclinical research concerning soluble TCR-based protein biologics, describes the clinical progress, discusses the quality control of TCR drugs, and explores the challenges and possible future improvements for soluble TCR-based protein biologics.<\/jats:p>","DOI":"10.3390\/ijms27198859","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:31:31Z","timestamp":1791203491000},"page":"8859","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bench-to-Bedside Perspectives on the Development of Soluble TCR-Based Protein Biologics: Current Landscape, Control Strategy and Future Direction"],"prefix":"10.3390","volume":"27","author":[{"given":"Jingyi","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China"},{"name":"State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxin","family":"An","sequence":"additional","affiliation":[{"name":"School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China"},{"name":"State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanfei","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyu","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1056\/NEJMra1706169","article-title":"Chimeric antigen receptor therapy","volume":"379","author":"June","year":"2018","journal-title":"N. 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