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This review outlines the development, structural formats, and therapeutic potential of various TCE platforms, including bispecific (BiTEs) and trispecific T-cell engagers (TriTEs), dual affinity re-targeting (DART), and other emerging formats. We also highlight the clinical success in treating hematologic malignancies as demonstrated by agents such as blinatumomab and teclistamab. We also discussed the ongoing challenges in solid tumors, such as antigen heterogeneity and the immunosuppressive tumor microenvironment. A comparative analysis with CAR-T cell therapies is provided, with a focus on efficacy, safety, toxicity, resistance, and cost. Strategies to increase specificity and reduce toxicity, such as tumor-selective activation (e.g., XPATs), CD3 affinity tuning, and multifunctional constructs, are discussed. Future directions include AI-driven design, synthetic biology, and potential applications beyond oncology, including autoimmune and infectious diseases. As scalable, off-the-shelf therapeutics, T-cell engagers are poised to become essential tools in personalized and accessible cancer treatment.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1755512","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:06:58Z","timestamp":1780466818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["T-cell engagers in cancer immunotherapy: mechanisms, challenges, and future perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Kaaviyaa","family":"Muthughavi","sequence":"first","affiliation":[{"name":"School of Biochemistry and Cell Biology, University College Cork","place":["Cork, Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Khokhar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["Jodhpur, Rajasthan, 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