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Antibody–drug conjugates (ADCs) deliver cytotoxic payloads to antigen-positive cells and can partially address heterogeneity via bystander killing. Immunofusion proteins (IFPs) localize immune activation or retarget effectors within immunologically “cold”, stroma-rich tumors. This review integrates clinical and translational advances in ADCs and emerging IFP platforms across GI cancers, emphasizing organ-dependent efficacy–toxicity trade-offs, convergent resistance pathways, and the proposed “immunocytotoxic convergence” ADC→IFP prime–amplify hypothesis requiring biomarker-enabled validation.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/immuno-cytotoxic-convergence-integrating-antibody-drug-conjugates-and-immunofusion-proteins-to-overcome-resistance-in-gastrointestinal-cancers/349200/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/immuno-cytotoxic-convergence-integrating-antibody-drug-conjugates-and-immunofusion-proteins-to-overcome-resistance-in-gastrointestinal-cancers/349200.png","ImageObject",300,407,{"name":92,"@type":93},"Cart","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the review address in gastrointestinal (GI) cancers?","Question",{"text":112,"@type":113},"It addresses treatment resistance driven by molecular heterogeneity and strongly immunosuppressive tumor microenvironments that limit effective therapy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do antibody–drug conjugates (ADCs) and immunofusion proteins (IFPs) differ in their therapeutic design?",{"text":117,"@type":113},"ADCs deliver cytotoxic payloads to antigen-positive cells and can promote bystander killing, while IFPs focus on localizing immune activation and retargeting immune effectors in immunologically “cold” stroma-rich tumors.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the proposed “immunocytotoxic convergence” concept?",{"text":121,"@type":113},"It proposes that under specific conditions, ADC-driven cytoreduction and immunogenic stress signatures may transiently improve immune accessibility, creating a window for subsequent immune amplification by IFPs.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},349200,1790138494,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},18829141979164,"https://eur-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Wu et al. Journal of Hematology & Oncology (2026) 19:32 [https://doi.org/10.1186/s13045-026-01795-6](https://doi.org/10.1186/s13045-026-01795-6)  \nJournal of Hematology & Oncology  \nREVIEW Open Access  \nImmuno-cytotoxic convergence: integrating antibody‒drug conjugates and immunofusion proteins to overcome resistance in gastrointestinal cancers  \nShenghong Wu1,2†, Ran Cui3†, Kangnan Zhao1, Zhen Yang1,2, Zihan Yi3, Weiwei Cao3,4 and Li Ye1*  \nAbstract  \nGastrointestinal (GI) cancers account for nearly one-third of cancer-related deaths worldwide and often remain difficult to treat because of pronounced molecular heterogeneity and strongly immunosuppressive tumor microenvironments (TMEs) . Antibody–drug conjugates (ADCs) deliver highly potent cytotoxic payloads to antigen-positive cells and may partially address intratumoral heterogeneity through bystander killing. In contrast, immunofusion proteins (IFPs)—including cytokine–antibody fusions and T-cell–redirecting modalities such as bispecific T-cell engagers—are designed to localize immune activation and/or retarget immune effectors within immunologically “cold”, stroma-rich tumors. In this review, we integrate recent clinical and translational advancesin ADCs and emerging IFP platforms across gastric, colorectal, pancreatobiliary and hepatocellular cancers, with particular attention to organ-dependent efficacy–toxicity trade-offs (e. g., interstitial lung disease (ILD) associated with DXd-based ADCs; cytokine release syndrome with T-cell engagers) and convergent resistance mechanisms, including antigen loss, impaired payload processing, immune exhaustion, and stromal exclusion. We further propose “immunocytotoxic convergence” as a hypothesis-generating and testable working model: under specific conditions, ADC-driven cytoreduction, immunogenic stress signatures consistent with immunogenic cell death (ICD), and/or stromal remodeling may transiently improve immune accessibility and thereby create a window for subsequent immune amplification by IFPs. Direct clinical evidence for an explicit ADC→ IFP Prime–Amplify sequence in GI cancers remains limited. We therefore summarize the current evidence base, define key failure modes and safety constraints, and outline biomarker-enabled experimental and early-phase trial approaches needed to validate—or falsify—this sequencing concept.  \nKeywords Antibody‒Drug Conjugate, Immunofusion Protein, Gastrointestinal Cancer, Targeted Therapy, Drug Resistance  \n†Shenghong Wu and Ran Cui contributed equally to this work.  \n*Correspondence: Li Ye [lye@must.edu. mo](lye@must.edu. mo)  \n1School of Pharmacy, Faculty of Medicine & Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau 999078, Taipa, China  \n2Department of Medical Oncology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People’s Hospital South Campus, Shanghai 201499, China  \n3Faculty of Medicine, Macau University of Science and Technology, Macau 999078, Taipa, China  \n4State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau 999078, Taipa, China  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your inten","cbCaiqxqv4Qf6LSR","https://ap.wps.com/l/cbCaiqxqv4Qf6LSR","pdf",5838137,29,"English","# Abstract\n# Background","[{\"question\":\"What problem does the review address in gastrointestinal (GI) cancers?\",\"answer\":\"It addresses treatment resistance driven by molecular heterogeneity and strongly immunosuppressive tumor microenvironments that limit effective therapy.\"},{\"question\":\"How do antibody–drug conjugates (ADCs) and immunofusion proteins (IFPs) differ in their therapeutic design?\",\"answer\":\"ADCs deliver cytotoxic payloads to antigen-positive cells and can promote bystander killing, while IFPs focus on localizing immune activation and retargeting immune effectors in immunologically “cold” stroma-rich tumors.\"},{\"question\":\"What is the proposed “immunocytotoxic convergence” concept?\",\"answer\":\"It proposes that under specific conditions, ADC-driven cytoreduction and immunogenic stress signatures may transiently improve immune accessibility, creating a window for subsequent immune amplification by IFPs.\"}]","Immuno-cytotoxic convergence - integrating antibody-drug conjugates and immunofusion proteins to overcome resistance in gastrointestinal cancers | PDF",1790082180,73]