[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-346267-105":59,"doc-detail-346267-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","reversing-enhancer-rnamediated-ikbke-gene-repression-enables-synthetic-anticancer-immunity-in-prostate-cancer-models","Reversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models","","Immunotherapy shows limited success in prostate cancer despite effectiveness in other malignancies, with mechanisms largely unresolved. Androgen receptor pathway inhibitor (ARPI) combined with irradiation (IR) induces robust anticancer immunity in both patients and mouse models. Androgen-activated AR suppresses innate immune signaling by repressing IKBKE via HDAC2 interaction with an IKBKE enhancer RNA (IKBKEeRNA). ARPI triggers IKBKE derepression and amplifies IR-driven innate responses through RIG-I and MDA5 sensors. IKBKE-e ablation further boosts innate immunity in cultured cells and in vivo, identifying AR–HDAC2–IKBKEeRNA as actionable intrinsic immune suppressors.",{"@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":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/reversing-enhancer-rnamediated-ikbke-gene-repression-enables-synthetic-anticancer-immunity-in-prostate-cancer-models/346267/",{"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/reversing-enhancer-rnamediated-ikbke-gene-repression-enables-synthetic-anticancer-immunity-in-prostate-cancer-models/346267.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why have immune checkpoint inhibitors performed poorly in prostate cancer clinical trials?","Question",{"text":112,"@type":113},"Multiple large phase III trials of PD-1/PD-L1 blockade and dual-checkpoint approaches reported poor response rates in prostate cancer, indicating unresolved mechanisms and limited efficacy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does androgen receptor signaling suppress innate immune activity in this study?",{"text":117,"@type":113},"Androgen-activated AR induces IKBKE gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKEeRNA), thereby suppressing innate immune signaling.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the mechanistic impact of combining ARPI with irradiation?",{"text":121,"@type":113},"ARPI causes IKBKE derepression and enhances an IR-induced innate immune response by activating RIG-I and MDA5 dsRNA sensors, promoting anticancer immunity.","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},346267,1790193855,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"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},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","The Journal of Clinical Investigation RESEAR CH ARTICLE  \nReversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models  \nXiang Li,1,2,3 Rui Sun,1,3 Hao Li,1,3 Jacob J. Orme,3,4 Xu Zhang,3,5 Yu Hou,6 Sean S. Park,7 Yu Zhang,1,3 Yi He,8 Liguo Wang,9 Veronica Rodriguez-Bravo,3 Josep Domingo-Domenech,3 Shancheng Ren,10 Dan Xia,1 Guanghou Fu,1 Zhankui Jia,2 and Haojie Huang1,3  \n1Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 2Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 3Department of Biochemistry and Molecular Biology, and 4Department of Oncology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA. 5Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA. 6Department of Pulmonology, Children’s Hospital, National Clinical Research Center for Child Health, Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China. 7Department of Radiation Oncology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA. 8The First Hospital of Jiaxing, Jiaxing, China. 9Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA. 10Department of Urology, Changzheng Hospital, Shanghai, China.  \nImmunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKEeRNA, or IKBKE-e) . ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinasesubunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically “cold” cancers such as prostate cancer.  \nIntroduction  \nImmunotherapy has revolutionized the treatment of many cancers (1, 2) . The blockade of programmed death 1 (PD-1) and programmed death ligand 1/-2 (PD-L1/2) interaction has been the major immunotherapy paradigm with hundreds of approved clinical indications. Additional immune checkpoint inhibitors (ICIs) blocking cell-cell signaling by targeting CTLA4, LAG-3, and others have also shown promise in multiple indications (3–5) . Unfortunately, these approaches have failed in prostate cancer clinical trials. Large phase III trials of single-agent pembrolizumab in KEYNOTE-199 (6) and dual-checkpoint blockade with nivolumaband ipilimumab in CheckMate 650 (7) have reported poor response rates. Methods to overcome the limitations of prostate cancer–targeted ICI are needed.  \nAuthorship note: XL, RS, HL, and JJO contributed equally to this work.  \nConflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2026, Li et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nSubmitted: January 3, 2025; Accepted: November 13, 2025;  \nPublished: January 16, 2026.  \nReference information: J Clin Invest. 2026;136(2):e190928 .  \n[https://doi.org/10.1172/JCI190928](https://doi.org/10.1172/JCI190928) .  \nThe androge","cbCais2Mb7feLJMn","https://ap.wps.com/l/cbCais2Mb7feLJMn","pdf",11599062,18,"English","# Introduction\n## Immunotherapy challenges in prostate cancer\n## Rationale for targeting AR signaling and innate immunity","[{\"question\":\"Why have immune checkpoint inhibitors performed poorly in prostate cancer clinical trials?\",\"answer\":\"Multiple large phase III trials of PD-1/PD-L1 blockade and dual-checkpoint approaches reported poor response rates in prostate cancer, indicating unresolved mechanisms and limited efficacy.\"},{\"question\":\"How does androgen receptor signaling suppress innate immune activity in this study?\",\"answer\":\"Androgen-activated AR induces IKBKE gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKEeRNA), thereby suppressing innate immune signaling.\"},{\"question\":\"What is the mechanistic impact of combining ARPI with irradiation?\",\"answer\":\"ARPI causes IKBKE derepression and enhances an IR-induced innate immune response by activating RIG-I and MDA5 dsRNA sensors, promoting anticancer immunity.\"}]","Reversing enhancer RNA–mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models | PDF",1790060723,45]