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The study re-engineers the mouse MDM2–HSC70 tumor-promoting axis using an artificial selenoprotein Path-editor, which splits into PMI and PPI peptides inside cells. PMI blocks MDM2-driven p53 degradation and upregulates HSC70, while PPI binds HSC70 to enable selective PD-L1 degradation. In microsatellite-stable colorectal cancer models, Path-editor attenuates PD-L1, reverses immune evasion, inhibits tumor growth, and maintains high biosafety, proposing rapid design of tumor-specific pathway editors via selenium-assisted strategy.",{"@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/from-foe-to-friend-rewiring-oncogenic-pathways-through-artificial-selenoprotein-to-combat-immune-resistant-tumor/411430/",{"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/from-foe-to-friend-rewiring-oncogenic-pathways-through-artificial-selenoprotein-to-combat-immune-resistant-tumor/411430.png","ImageObject",300,407,{"name":92,"@type":93},"McQueen","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main therapeutic idea in this study?","Question",{"text":112,"@type":113},"The work focuses on reprogramming an oncogenic signaling pathway so it produces anti-tumor immune effects rather than tumor-promoting activity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does Path-editor work after entering cells?",{"text":117,"@type":113},"Path-editor decomposes into PMI and PPI peptides: PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression, while PPI binds HSC70 to enable selective degradation of PD-L1.",{"name":119,"@type":110,"acceptedAnswer":120},"What results were observed in microsatellite-stable colorectal cancer models?",{"text":121,"@type":113},"Path-editor reduced PD-L1 expression, reversed immune evasion in CT26 allografts and patient-derived tumor xenografts, inhibited tumor progression, and showed high biosafety.","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},411430,1790904489,{"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":19,"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,"preview_page_count":4},5909890329169,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","Journal of Pharmaceutical Analysis 15 (2025) 101322  \nContents lists available at ScienceDirect  \nJournal of Pharmaceutical Analysis  \njournal [homepage:](homepage: www. elsevier. com/locate/jpa)[ www. elsevier. com/locate/jpa](homepage: www. elsevier. com/locate/jpa)  \n| Original article\u003Cbr>From foe to friend: Rewiring oncogenic pathways through artificialselenoprotein to combat immune-resistant tumor\u003Cbr>Weiming You a, b, 1, Zhengjun Zhou c, 1, Zhanfeng Li d, 1, Jin Yan a, b, **, Yang Wang a, b, *\u003Cbr>a Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China\u003Cbr>b National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China\u003Cbr>c Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China d Department of Medical Oncology and Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China |  |  | |\n| --- | --- | --- | --- |\n| a r t i c l e i n f o |  | a b s t r a c t |  |\n| Article history:\u003Cbr>Received 18 January 2025\u003Cbr>Received in revised form\u003Cbr>14 April 2025\u003Cbr>Accepted 21 April 2025\u003Cbr>Available online 25 April 2025 |  | Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention, without significant off-target effects. Although reprogramming multioncoprotein interactions in a single signaling pathway axis has been shown to achieve sustained efficacy, there are several challenges that limit its clinical application. Herein, we transformed the mouse double minute 2 homolog (MDM2)-heat shock cognate protein 70 (HSC70) axis, a tumor-promoting pathway, into an activator of anti-tumor immunity using the Path-editor, an artificial selenoprotein. Once it enters the cell, Path-editor decomposes into PMI and PPI peptides: PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression, while PPI binds to HSC70, enabling its ability to selectively degrade the programmed cell death ligand 1 (PD-L1). As a proof of concept, we tested its performance in microsatellite-stable (MSS) colorectal cancer, which typically displays limited responsiveness to immunotherapy. The results indicated that Path-editor effectively attenuated PD-L1 expression and reversed immune evasion in both CT26 allografts and humanized patient-derived tumor xenograft (PDX) models, thereby inhibiting tumor progression with high biosafety. Therefore, this paper introduces Path-editor as a paradigm for reprogramming oncogenic multi-protein pathways, utilizing selenium-assisted approach to achieve the rapid design of tumor-specific pathway editors. This strategy is expected to reverse immune escape in MSS colorectal cancer and treat difficult malignancies.\u003Cbr>© 2025 The Authors. Published by Elsevier B.V. on behalf of Xi’an Jiaotong University. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). |  |\n| Keywords: Reprogramming\u003Cbr>Pro-oncogenic pathways Anti-tumor immunity Artificial microprotein Cancer therapy |  |  |  |\n\n1. Introduction  \nThe proliferation and survival processes of cancer cells are often driven by the increased activity of pro-oncogenic signaling pathways, as well as enhanced protein expression [1,2]. A major pathway implicated in the development of cancers is the mouse double minute 2 homolog (MDM2) pathway, which is frequently upregulated in various malignancies and known to promote tumorigenesis  \nPeer review under responsibility of Xi'an Jiaotong University.  \n* Corresponding author. Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.  \n** Corresponding author. Department of Infectious Diseases, The Second Affiliated Hosp","cbCaijLbspWkwfCe","https://ap.wps.com/l/cbCaijLbspWkwfCe","pdf",10537670,15,"English","# Introduction\n# Abstract\n# Keywords","[{\"question\":\"What is the main therapeutic idea in this study?\",\"answer\":\"The work focuses on reprogramming an oncogenic signaling pathway so it produces anti-tumor immune effects rather than tumor-promoting activity.\"},{\"question\":\"How does Path-editor work after entering cells?\",\"answer\":\"Path-editor decomposes into PMI and PPI peptides: PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression, while PPI binds HSC70 to enable selective degradation of PD-L1.\"},{\"question\":\"What results were observed in microsatellite-stable colorectal cancer models?\",\"answer\":\"Path-editor reduced PD-L1 expression, reversed immune evasion in CT26 allografts and patient-derived tumor xenografts, inhibited tumor progression, and showed high biosafety.\"}]","From foe to friend - Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor | PDF",1790588543,38]