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These changes disrupt luminal identity, activate compensatory pathways (FGFR-MAPK, mTORC1-MYC), and sculpt immunosuppression through CCL2 secretion, enabling squamous/basal traits, metabolic reprogramming, stemness, and early visceral metastasis, while challenging direct targeting of key transcription factors.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/deciphering-double-negative-prostate-cancer-from-aggressive-subtype-to-novel-therapeutic-paradigms/356727/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/deciphering-double-negative-prostate-cancer-from-aggressive-subtype-to-novel-therapeutic-paradigms/356727.png","ImageObject",300,407,{"name":42,"@type":43},"วิน","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-02","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What defines double-negative prostate cancer (DNPC)?","Question",{"text":63,"@type":64},"DNPC is defined by absence of androgen receptor (AR) expression and neuroendocrine markers. 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Cell Communication and Signaling (2026) 24:264  \n[https://doi.org/10.1186/s12964-026-02795-2](https://doi.org/10.1186/s12964-026-02795-2)  \nCell Communication and Signaling  \nREVIEW Open Access  \nDeciphering double-negative prostate cancer:  from aggressive subtype to novel therapeutic paradigms  \nJie Wang1,2†, Ruicheng Wu2,3†, Zhouting Tuo4†, Uzoamaka Adaobi Okoli3,5, Zhipeng Wang6,  \nPremkamon Chaipanichkul7, Siang Boon Koh8, Dengxiong Li9, Zhaojie Lyu10, Cheema Umber3*, Qi Zhang1* and Dechao Feng1,3*  \nAbstract  \nDouble-negative prostate cancer (DNPC), defined by the absence of androgen receptor expression and neuroendocrine markers, represents a clinically aggressive and molecularly distinct subtype of metastatic castration-resistant prostate cancer. Typically emerging after failure of second-generation androgen receptor pathway inhibitors, DNPC portends a dismal prognosis with intrinsic resistance to conventional therapies. This malignancy arises through profound lineage plasticity, driven by epigenetic dysregulation including KMT2C loss and PRC1 complex activation, alongside transcriptional rewiring orchestrated by master regulators like Delta Np63 and KLF5 . These alterations dismantle luminal identity, establish compensatory signaling pathways such as FGFR-MAPK and mTORC1-MYC and actively sculpt an immunosuppressive tumor microenvironment, notably through CCL2 chemokine secretion. The resulting phenotype features squamous/basal differentiation, metabolic reprogramming, stemness properties, and early visceral metastasis. Despite molecular characterization revealing recurrent alterations like PTEN and RB1 co-loss and CHD7 amplification, therapeutic translation faces significant hurdles, particularly the difficulty of directly targeting key transcription factors. Innovative strategies are essential, including degrader molecules against master regulators, exploiting vulnerabilities linked to specific genomic losses, combinatorial targeting of parallel survival pathways, and novel immunotherapies aimed at disrupting the immunosuppressive niche. Overcoming diagnostic limitations and designing biomarker-stratified clinical trials are critical next steps. DNPC exemplifies adaptive cancer evolution under therapeutic pressure, demanding multidisciplinary efforts to decipher its complexities and translate these insights into effective therapeutic paradigms for this lethal variant. Keywords Double-negative prostate cancer, Lineage plasticity, Epigenetic regulation, Therapeutic resistance  \n†Jie Wang, Ruicheng Wu and Zhouting Tuo contributed equally to this work.  \n*Correspondence: Cheema Umber [u.cheema@ucl.ac.uk](u.cheema@ucl.ac.uk)[ ](u.cheema@ucl.ac.uk)Qi Zhang [zhangqi1@hmc.edu.cn](zhangqi1@hmc.edu.cn)[ ](zhangqi1@hmc.edu.cn)Dechao Feng [dechao.feng@ucl.ac.uk](dechao.feng@ucl.ac.uk)  \nFull list of author information is available at the end of the article  \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 intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/li","cbCaikMNuAjInQGI","https://ap.wps.com/l/cbCaikMNuAjInQGI","pdf",4083166,15,"English","# Abstract\n## Introduction\n### Double-negative prostate cancer definition and clinical behavior\n### Emergence after AR-pathway inhibitor failure\n### Distinct molecular signature and lineage shift\n### Cellular origin and transdifferentiation model","[{\"question\":\"What defines double-negative prostate cancer (DNPC)?\",\"answer\":\"DNPC is defined by absence of androgen receptor (AR) expression and neuroendocrine markers. It represents a clinically aggressive, molecularly distinct subtype of metastatic castration-resistant prostate cancer.\"},{\"question\":\"Why does DNPC resist conventional therapies?\",\"answer\":\"DNPC emerges after failure of second-generation AR-pathway inhibitors and shows intrinsic resistance to conventional treatments. Its resistance is linked to lineage plasticity, epigenetic dysregulation, and transcriptional rewiring that dismantle luminal identity and establish compensatory survival pathways.\"},{\"question\":\"Which biological processes are highlighted as key drivers of DNPC development?\",\"answer\":\"The document emphasizes profound lineage plasticity driven by epigenetic dysregulation (including KMT2C loss and PRC1 complex activation) and transcriptional rewiring by regulators such as Delta Np63 and KLF5. These alterations also shape an immunosuppressive tumor microenvironment through mediators like CCL2.\"}]","Deciphering double-negative prostate cancer - from aggressive subtype to novel therapeutic paradigms | PDF",1790126966,38]