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This work presents a dual membrane receptor degradation strategy using Folate Receptor α (FRα) to build FolTAC-dual degraders that selectively and simultaneously degrade EGFR/HER2 and PD-L1/VISTA. Modular optimization identifies a “string” format as most effective, with ~85% higher EGFR-binding affinity than knob-into-hole. Proof-of-concept models show reversal of resistance in HER2-positive breast cancer and rejuvenated immune responses in PD-L1 antibody-resistant mice.",{"@graph":69,"@context":121},[70,84,104],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/dual-membrane-receptor-degradation-via-folate-receptor-targeting-chimera/376368/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/dual-membrane-receptor-degradation-via-folate-receptor-targeting-chimera/376368.png","ImageObject",300,407,{"name":92,"@type":93},"Anna Hans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24",true,{"@type":101,"interactionType":102,"userInteractionCount":8},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"What problem does the study address in cancer therapy?","Question",{"text":111,"@type":112},"The study addresses cancer drug resistance that arises from cross-talk among membrane-bound receptors, which can undermine mono-targeted therapies.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"How does FolTAC-dual work mechanistically?",{"text":116,"@type":112},"FolTAC-dual is engineered to selectively and simultaneously degrade two receptor pairs by leveraging Folate Receptor α (FRα)-mediated endocytosis.",{"name":118,"@type":109,"acceptedAnswer":119},"What were the key findings from the proof-of-concept experiments?",{"text":120,"@type":112},"EGFR and HER2 FolTAC-dual counteracted resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenated immune responses in PD-L1 antibody-resistant syngeneic mouse models.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},376368,1790270188,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},5909892332657,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Article [https://doi.org/10.1038/s41467-025-63882-5](https://doi.org/10.1038/s41467-025-63882-5)  \nDual membrane receptor degradation via folate receptor targeting chimera  \nReceived: 13 February 2025  \n\n| Accepted: 26 August 2025 |\n| --- |\n| |\n| Check for updates |\n\nZhen Wang 1,11, Zhixin Li2,3, Jenny Högström 4, Hiroyuki Inuzuka1, Rui Jing5, Peiqiang Yan1, Tao Hou1, Yihang Qi 1, Daoyuan Huang1, Jingchao Wang1, Ting Wu6,7,8, Xiaoying Shi 9, Bolin Liu 10, Taru Muranen 4,  \nDingpeng Zhang 1,11  & Wenyi Wei 1   \nCancer drug resistance poses a significant challenge in oncology, often driven by intricate cross-talk among membrane-bound receptors that compromise mono-targeted therapies. We develop a dual membrane receptor degradation strategy leveraging Folate Receptor α (FRα) to address this issue. Folate Receptor α Targeting Chimeras-dual (FolTAC-dual) are engineered degraders designed to selectively and simultaneously degrade distinct receptor pairs: (1) EGFR/HER2 and (2) PD-L1/VISTA. Through modular optimization of modality configurations and geometries, we identify the “string” format as the most effective construct. Mechanistic studies demonstrate an ~85% increase in EGFR-binding affinity compared to the conventional knob-into-hole design, likely contributing to the improved efficiency of dual-target degradation. Proof-of-concept studies reveal that EGFR and HER2 FolTAC-dual effectively counteracts resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenates immune responses in PD-L1 antibody-resistant syngeneic mouse models. These findings establish FolTAC-dual as a promising dual-degradation platform for clinical translation.  \nCancer drug resistance is a persistent barrier to the success of targeted therapies, often arising from compensatory signaling between membrane-bound receptors that bypass mono-targeted inhibition1–4. For instance, resistance to HER2-targeted therapies like Trastuzumab frequently involves upregulated EGFR or HER3 signaling5–10, while immunotherapy resistance is driven by alternative immune checkpoints, such as VISTA, compensating for PD-L1 blockade11–15. These mechanisms highlight the pressing need for innovative multi-receptor targeting approaches that mitigate redundancy while maintaining  \nspecificity. Bispecific antibodies have been developed to block two receptor-mediated pathways16. However, the resistance problem remains a potential hurdle for this strategy17. These limitations highlight the need for alternative approaches—specifically, dual-targeted therapeutic platforms that eliminate, rather than merely inhibit, key membrane receptors to more effectively overcome resistance mechanisms.  \nEmerging technologies such as LYTACs18 or LYTAC-like platforms19 have demonstrated the potential for targeted membrane  \n1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 3Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA. 4Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 5Houston Methodist Cancer Center/Weill Cornell Medicine, Houston, TX, USA. 6Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA. 7Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 8Department of Pediatrics, Harvard Medical School, Boston, MA, USA. 9Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA. 10Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, USA. 11These authors contributed equally: Zhen Wang, Dingpeng Zhang. e-mail: [dzhang13@bidmc.harvard.edu](dzhang13@bidmc.harvard.edu); [wwei2@bidmc.harvard.edu](wwei2@bidmc.harvard.edu)  \nprotein degradation. The LYTAC is developed based o","cbCaidqCFasR4lvE","https://ap.wps.com/l/cbCaidqCFasR4lvE","pdf",4015380,17,"English","# Introduction\n# Dual membrane receptor degradation strategy\n# FolTAC-dual design and optimization\n# Mechanistic and proof-of-concept results\n# Rationale for using FRα","[{\"question\":\"What problem does the study address in cancer therapy?\",\"answer\":\"The study addresses cancer drug resistance that arises from cross-talk among membrane-bound receptors, which can undermine mono-targeted therapies.\"},{\"question\":\"How does FolTAC-dual work mechanistically?\",\"answer\":\"FolTAC-dual is engineered to selectively and simultaneously degrade two receptor pairs by leveraging Folate Receptor α (FRα)-mediated endocytosis.\"},{\"question\":\"What were the key findings from the proof-of-concept experiments?\",\"answer\":\"EGFR and HER2 FolTAC-dual counteracted resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenated immune responses in PD-L1 antibody-resistant syngeneic mouse models.\"}]","Dual membrane receptor degradation via folate receptor targeting chimera | PDF",1790218435,43]