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TCEs form immunological synapses to trigger potent immune responses, with proven efficacy in blood cancers; research expands their use to solid tumors via innovative molecular design and improved safety profiles. Beyond oncology, TCEs hold promise in autoimmune disorders by eliminating autoreactive cells, offering novel avenues for diseases like lupus. However, achieving optimal outcomes without disrupting immune homeostasis remains a challenge. Key obstacles\u2014on-target off-tumor toxicity, cytokine release syndrome, tumor antigen loss, and T cell exhaustion\u2014limit broader adoption. Current research addresses these via enhanced specificity, optimized design, improved druggability, and synergistic combinations. This review analyzes TCEs\u2019 mechanisms, challenges, innovations and applications, highlights our pipeline advances, and advocates sustained innovation to broaden TCE use across diseases.<\/jats:p>","DOI":"10.1093\/abt\/tbaf026","type":"journal-article","created":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T12:55:55Z","timestamp":1766235355000},"page":"58-69","source":"Crossref","is-referenced-by-count":5,"title":["Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy"],"prefix":"10.1093","volume":"9","author":[{"given":"Xiaoqiang","family":"Kang","sequence":"first","affiliation":[{"name":"Nanjing Leads Biolabs , Nanjing, 210031 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1450-2578","authenticated-orcid":false,"given":"Yue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Strategic & Intelligence Department, Nanjing Leads Biolabs , Nanjing, 210031 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