{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:30:57Z","timestamp":1787243457041,"version":"build-2736575974"},"reference-count":107,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Khalid University\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/052kwzs30","award":["RGP2\/257\/45"],"award-info":[{"award-number":["RGP2\/257\/45"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: T-cell-engaging bispecific antibodies (TCEs) have transformed haematological malignancy treatment (blinatumomab &gt; 40% complete remission), yet solid tumour efficacy remains limited (&lt;15% response rates) due to antigen heterogeneity, immunosuppressive microenvironments, and T-cell dysfunction. Systematic molecular engineering, biomarker-driven patient selection, and rational tumour microenvironment modulation are now collectively transforming TCEs from experimental agents into an adaptable platform therapy for solid tumours. Methods: Review of 55 phase I\u2013III trials of CD3-based TCEs in solid tumours, including tarlatamab (DLL3-targeted, small-cell lung cancer) and xaluritamig (STEAP1-targeted, prostate cancer). Analysis of next-generation engineering strategies and resistance mechanisms via genomic and immunohistochemical data. Result: Response rates now approach ~40% in selected settings, marking an inflection point. In extensive-stage small-cell lung cancer, tarlatamab achieved ~40% responses with definitive survival benefit (phase III HR 0.60, 95% CI 0.47\u20130.77; p &lt; 0.001; median OS 13.6 months). In metastatic castration-resistant prostate cancer, xaluritamig produced ~41% responses in heavily pretreated patients. Step-up dosing reduced severe cytokine release syndrome to &lt;1% (as low as 0.6% with teclistamab), enabling outpatient administration. Neurological adverse events require monitoring but are less frequent than with cellular therapies. Together these results mark a decisive transition from proof-of-concept to clinically validated platform therapy. Discussion: Three resistance mechanisms limit durability: (i) antigen heterogeneity (28\u201360% of progressors develop antigen-negative subclones); (ii) immunosuppressive microenvironments (stromal barriers, myeloid-derived suppressor cells, hypoxia); (iii) T-cell exhaustion (PD-1\/TIM-3\/LAG-3 co-expression). Conclusions: Next-generation TCE platforms integrating conditional activation, cytokine payloads, and checkpoint modulation\u2014deployed with biomarker-guided selection and TME-modulating combinations\u2014represent a transformative therapeutic strategy. With tarlatamab\u2019s phase III survival benefit establishing clinical proof-of-concept, and pivotal trials underway for xaluritamig and next-generation agents, TCEs are positioned to become standard-of-care platform therapies in biomarker-defined solid tumours by 2028\u20132030.<\/jats:p>","DOI":"10.3390\/cancers18071088","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:32:47Z","timestamp":1774611167000},"page":"1088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Precision-Engineered CD3 T-Cell Engagers for Solid Tumours: Conditional Activation, Microenvironment Modulation, and Clinical Translation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-4129","authenticated-orcid":false,"given":"Md.","family":"Zeyaullah","sequence":"first","affiliation":[{"name":"Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-1913","authenticated-orcid":false,"given":"Abdullah M.","family":"AlShahrani","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Suhail","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3353-0457","authenticated-orcid":false,"given":"Md Faruque","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, College of Nursing and Health Sciences, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-2607","authenticated-orcid":false,"given":"Abdelrhman A. G.","family":"Altijani","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9286-877X","authenticated-orcid":false,"given":"Awad Osman Abdalla","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Operations, College of Applied Medical Sciences, Khamis Mushait Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hytham","family":"Hummad","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Operations, College of Applied Medical Sciences, Khamis Mushait Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3038-3105","authenticated-orcid":false,"given":"Ali","family":"Mohieldin","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences, Khamis Mushayt Campus, King Khalid University (KKU), Abha 62561, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-5238","authenticated-orcid":false,"given":"S. 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