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It expands CD46’s roles across complement control, T cell modulation, immunoinflammatory effector functions, autophagy, and an intracellular complement system. The work connects dysregulated CD46 expression with malignant transformation and metastasis potential, highlighting CD46 as a pathogen entry factor and as a therapeutic target using CD46-directed viral vectors and antibody-drug conjugates. It also outlines complement biology, CD46 identification, and isoform structure.",{"@graph":69,"@context":115},[70,84,106],{"@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/the-multiverse-of-cd46-and-oncologic-interactions-review/374405/",{"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/the-multiverse-of-cd46-and-oncologic-interactions-review/374405.png","ImageObject",300,407,{"name":92,"@type":93},"\tJames","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109],{"name":110,"@type":111,"acceptedAnswer":112},"How was CD46 identified and what explains its multiple isoforms?","Question",{"text":113,"@type":114},"CD46 was initially identified as a C3b- and C4b-binding complement receptor/regulatory protein using affinity chromatography and later shown to serve as a cofactor for factor I. Its multiple isoforms arise from alternative splicing of a single ~43 kb gene with 14 exons and 13 introns, producing a family of four predominant isoforms.","Answer","https://schema.org",{"og:url":83,"og:type":117,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":119,"canonical":83},"index,follow",{"doc_id":121,"site_id":62},374405,1790884933,{"code":4,"msg":5,"data":124},{"doc_id":121,"user_id":125,"nickname":92,"user_avatar":126,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":127,"file_id":128,"file_url":129,"file_type":130,"file_size":131,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":105,"language":132,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":67,"update_tm":136,"read_time":137},2336474466412,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","The Journal of Clinical Investigation REVIEW SERIES: COMPLEMENT BIOLOGY AND THERAPEUTICS  \nSeries Editor: Claudia Kemper  \nThe multiverse of CD46 and oncologic interactions  \nM. Kathryn Liszewski and John P. Atkinson  \nDivision of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.  \nInitially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells  \nas a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a “pathogen” magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer biology. Numerous studies provide evidence of the association among elevated CD46 expression, malignant transformation, and metastasizing potential. These features, along with its roles as pathogen receptor, have made CD46 a target for cancer therapeutics. Thus, modified viral vectors (such as strains of adenovirus and measles virus) targeting CD46 currently are being exploited against a wide range of cancers. Another oncologic treatment utilizes a CD46-targeting human mAb as an antibody-drug conjugate. Herein, we review CD46 and its “multiverse” of cancer interactions.  \nIntroduction  \nCD46 (also called membrane cofactor protein [MCP]) plays multifaceted roles in health and disease. It was initially identified asa C3b-binding protein utilizing C3b and C3(H2O) affinity column chromatography (1) and was subsequently demonstrated to serve as a regulator of complement activation on host cells (refs. 1, 2 and reviewed in ref. 3) . We now know that CD46 is expressed on most cells, where it helps mitigate the activation of the complement system in order to focus and limit complement attack to invading pathogens and damaged tissue (3, 4) .  \nCD46 also is becoming recognized as a potential tumor target or prognostic indicator because complement (and CD46) expression is often dysregulated (i.e. , increased) during tumorigenesis (5, 6) . Clinical and experimental data support an association between higher expression and malignant transformation as well as potential to metastasize. To better understand CD46 as a player in cancer biology, it is helpful to have a more complete background (including structural and functional profiles) of this multitalented protein.  \nComplement and CD46. Complement activation leads to the rapid identification and destruction of invading pathogens (7) . The system also is a key mediator of local inflammation and a director of adaptive immunity (8) . Because of the complement system’s proinflammatory, immune-enhancing, and cell/tissue-damaging capabilities, nearly half of complement components function in its regulation/ inhibition. Indeed, this provides the basis for recognition of “self”from “nonself” in that self cells, bearing complement control pro-  \nConflict of interest: JPA is currently a consultant or on a scientific advisory board for Achillion Pharmaceuticals Inc. , Alexion Pharmaceuticals Inc. , Annexon Biosciences Inc. , Celldex, Kypha, and Q32 Bio and has stock, equity, or options in Broadwing Bio, Compliment Corporation, Gemini Therapeutics Inc. , Kypha Inc. , and Q32 Bio. Copyright: © 2025, Liszewski et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nReference information: J Clin Invest. 2025;135(9):e188355 .  \n[https://doi.org/10.1172/JCI188355](https://doi.org/10.1172/JCI188355) .  \nteins, are protected while nonself (e.g., bacteria and damaged cells) are attacked. Complement’s regulators are expressed in the fluid phase (plasma) and on cell membr","cbCaihoADsLe63z9","https://ap.wps.com/l/cbCaihoADsLe63z9","pdf",677625,"English","# Introduction\n## Complement and CD46\n## Identification and cloning","[{\"question\":\"How was CD46 identified and what explains its multiple isoforms?\",\"answer\":\"CD46 was initially identified as a C3b- and C4b-binding complement receptor/regulatory protein using affinity chromatography and later shown to serve as a cofactor for factor I. Its multiple isoforms arise from alternative splicing of a single ~43 kb gene with 14 exons and 13 introns, producing a family of four predominant isoforms.\"}]","The multiverse of CD46 and oncologic interactions - review | PDF",1790201597,28]