{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T22:33:58Z","timestamp":1792708438019,"version":"4.5.0"},"reference-count":179,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antibody-drug conjugates (ADCs) have transitioned from clinically marginal agents into a defining therapeutic class for solid tumor oncology. In DESTINY-Breast03, trastuzumab deruxtecan achieved a four-fold progression-free survival advantage over trastuzumab emtansine, attributable not to antibody engineering but to the linker-payload axis: a cleavable peptide linker and a topoisomerase I payload with bystander activity. Sacituzumab govitecan extends the same logic to Trop-2-positive disease via extracellular payload release, and the framework now spans breast, urothelial, gynecologic, lung, gastric, and colorectal cancers, with enfortumab vedotin plus pembrolizumab displacing platinum chemotherapy as first-line therapy for urothelial cancer in EV-302 (median overall survival 31.5 versus 16.1 months). This review synthesizes ADC biology along three analytical axes. The mechanistic axis links each linker-payload-DAR configuration to a specific tumor-biology barrier: vascular limitation, which delivers approximately 0.1% of the administered dose to tumor tissue; the binding-site barrier, which concentrates exposure at the perivascular margin; and antigen mosaicism, which defeats internalization-dependent killing. The translational axis examines resistance as a coordinated failure across antigen modulation, trafficking, efflux, apoptotic execution, and lysosomal processing. The clinical axis traces the platform\u2019s migration toward earlier-line and curative-intent settings. We close by examining whether the ADC delivery architecture translates to precision immunosuppression in autoimmune disease, where the glucocorticoid receptor modulator ADC ABBV-154 met placebo-controlled efficacy endpoints in rheumatoid arthritis but was discontinued because its benefit-risk profile did not differentiate it from existing biologic therapies.<\/jats:p>","DOI":"10.3390\/ijms27125196","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T09:46:54Z","timestamp":1780998414000},"page":"5196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Antibody-Drug Conjugates in Solid Tumor Oncology and the Frontier of Precision Immunosuppression: A Mechanistic, Translational, and Clinical Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9314-221X","authenticated-orcid":false,"given":"Ibraheem","family":"Masoud","sequence":"first","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1451-4217","authenticated-orcid":false,"given":"Nada Saed Homod","family":"Al Shaer","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Masoud","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9223-6826","authenticated-orcid":false,"given":"Ahmad","family":"Al Jandali","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0100-0159","authenticated-orcid":false,"given":"Abdulrahman","family":"Aldahash","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8048-9528","authenticated-orcid":false,"given":"Abdullah","family":"Jabri","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0546-4210","authenticated-orcid":false,"given":"Mohamed","family":"Alsharif","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fareeha","family":"Arshad","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itika","family":"Arora","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Imran","family":"Khan","sequence":"additional","affiliation":[{"name":"Research Center, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7536-910X","authenticated-orcid":false,"given":"Ahmed","family":"Yaqinuddin","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/s41571-021-00470-8","article-title":"Unlocking the potential of antibody-drug conjugates for cancer therapy","volume":"18","author":"Drago","year":"2021","journal-title":"Nat. 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