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This review summarises the structural and mechanistic basis of this strategy, its impact on TCR folding, CD3 assembly, mechanotransduction, and anti-tumour function, as well as current engineering approaches, persistent challenges, and future perspectives. Preclinical studies demonstrate improved heterodimer stability, reduced mispairing, higher surface expression, and enhanced signalling, positioning the second disulfide bond as a valuable complementary tool in next-generation TCR engineering.<\/jats:p>","DOI":"10.3390\/ph19060888","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering a Second Interchain Disulfide Bond in the \u03b1\u03b2 T-Cell Receptor Constant Domain: A Powerful Strategy to Enhance Stability, Pairing Fidelity, and Therapeutic Efficacy in TCR-T Cell Therapy"],"prefix":"10.3390","volume":"19","author":[{"given":"Nguyen Trung","family":"Quan","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0250-6693","authenticated-orcid":false,"given":"Xiangliang","family":"Lin","sequence":"additional","affiliation":[{"name":"Esco Aster Pte. 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