{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T15:14:14Z","timestamp":1780413254271,"version":"3.54.1"},"reference-count":93,"publisher":"Wiley","issue":"S1","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gastrointestinal (GI) malignancies remain a major cause of global cancer\u2010related mortality, especially in the setting of advanced or metastatic disease. Antibody\u2013drug conjugates (ADCs) have emerged as a promising class of targeted therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Through advances in antibody engineering, linker chemistry, and payload design, modern ADCs have demonstrated enhanced efficacy with manageable toxicity. Therapeutic agents such as trastuzumab deruxtecan and disitamab vedotin are currently approved ADCs in HER2\u2010overexpressing GI cancers, while multiple investigational ADCs targeting novel antigens, including Claudin 18.2, Claudin 6, B7\u2010H3, c\u2010MET, TROP2, and EGFR, are being evaluated in ongoing clinical trials. Innovative designs\u2014such as biparatopic and bispecific formats, dual or multipayload strategies, and the integration of novel cytotoxic modalities like radiotherapeutic agents\u2014are under active development to address resistance mechanisms, optimize payload delivery, and minimize off\u2010target toxicity. This review summarizes the structural components, mechanisms of action, approved agents, and evolving clinical pipeline of ADCs in GI cancers, highlighting both current challenges and emerging strategies aimed at expanding their therapeutic potential.<\/jats:p>","DOI":"10.1002\/cncr.70419","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T03:04:17Z","timestamp":1780369457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Emerging role of antibody\u2013drug conjugates in gastrointestinal malignancies"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4740-2256","authenticated-orcid":false,"given":"Uqba","family":"Khan","sequence":"first","affiliation":[{"name":"Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manish A.","family":"Shah","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.16930"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2402141"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2501912"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(23)00150\u2010x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(10)61121\u2010x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmc2408121"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010med\u2010050311\u2010201823"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201000947\u20107"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.09.016"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010025\u201001704\u20103"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010med\u2010061516\u2010121357"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmogo.2025.100154"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.268"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155510"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.27022"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1209124"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.687926"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238\u2010016\u20100323\u20100"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000850\u20102"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.268"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010015\u20101657\u20107"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114408"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.06.012"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.7b00243"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.mct\u201016\u20100688"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14418"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016211"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15061845"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.mct\u201020\u20100116"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2018.1531158"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.30.2365"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201300105"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i46.17532"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1949"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12966"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i26.5879"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2503119"},{"key":"e_1_2_7_40_1","unstructured":"FDA grants accelerated approval to fam\u2010trastuzumab deruxtecan\u2010nxki for unresectable or metastatic HER2\u2010positive solid tumors.2024[cited 2026 3\/9\/2026]; Available from:https:\/\/www.fda.gov\/drugs\/resources\u2010information\u2010approved\u2010drugs\/fda\u2010grants\u2010accelerated\u2010approval\u2010fam\u2010trastuzumab\u2010deruxtecan\u2010nxki\u2010unresectable\u2010or\u2010metastatic\u2010her2"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2022.2069883"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12214"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1132319"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.141.7.1539"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2024.155145"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.10.040"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010025\u201003783\u20108"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.am2024\u2010lb057"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004433\u20108"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.677"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/85339"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2023.189031"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379\u2010020\u20100587\u2010z"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.4_suppl.tps847"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.847835"},{"key":"e_1_2_7_56_1","article-title":"A bispecific antibody\u2013drug conjugate targeting EGFR and HER3 in metastatic esophageal squamous cell carcinoma: a phase 1b trial","author":"Liu C","year":"2025","journal-title":"Nat Med"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(24)00159\u20101"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2024.42.16_suppl.3515"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2020.1737490"},{"key":"e_1_2_7_60_1","first-page":"35","article-title":"Development of antibody\u2010based c\u2010Met inhibitors for targeted cancer therapy","volume":"4","author":"Lee D","year":"2015","journal-title":"ImmunoTargets Ther"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.16_suppl.8512"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.16_suppl.4148"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.4_suppl.438"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.1537"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.am2025\u20102872"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16071336"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.16_suppl.tps4207"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.mct\u201019\u20101004"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1177\/17588359241309461"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1039\/c6md00347h"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010021\u201000371\u20106"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201000966\u20104"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.20517\/cdr.2025.49"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.12.008"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1097\/ppo.0000000000000625"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.mct\u201015\u20101004"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132282"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.4155\/bio.15.84"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2108"},{"issue":"2","key":"e_1_2_7_80_1","article-title":"Design of cleavable linkers for antibody drug conjugates and evaluation of stability using radioimmunoconjugates","volume":"63","author":"Dominguez\u2010Garcia M","year":"2022","journal-title":"J Nucl Med"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1200\/edbk_390094"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030713"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00457"},{"key":"e_1_2_7_84_1","doi-asserted-by":"publisher","DOI":"10.4161\/self.1.4.13904"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.20517\/cdr.2025.148"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010024\u201002992\u2010x"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2024.2310890"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2025.43.16_suppl.3022"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.01.009"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010021\u201000354\u20100"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg1209"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2025.115608"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.117.206672"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.can\u201024\u20102266"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.70419","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cncr.70419","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.70419","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:51:18Z","timestamp":1780411878000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.70419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":93,"journal-issue":{"issue":"S1","published-print":{"date-parts":[[2026,6,1]]}},"alternative-id":["10.1002\/cncr.70419"],"URL":"https:\/\/doi.org\/10.1002\/cncr.70419","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"assertion":[{"value":"2025-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70419"}}