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Single-cell and spatial profiling reveal immune heterogeneity across patients, lesions, and disease progression, including hot minority regions with tertiary lymphoid structures and ICI responsiveness. Dissemination broadens suppressive myeloid programs, dysfunctional T-cell states, and lesion-specific immune invisibility, reshaped by standard therapies. A heterogeneity-aware, microenvironment-stratified framework is proposed, integrating biomarker-guided immunotherapy and barrier-matched strategies such as T-cell redirection and myeloid-modulating combinations.",{"@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/clinically-oriented-immune-heterogeneity-in-prostate-cancer-emerging-targets-and-strategies-mini-review/353765/",{"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/clinically-oriented-immune-heterogeneity-in-prostate-cancer-emerging-targets-and-strategies-mini-review/353765.png","ImageObject",300,407,{"name":92,"@type":93},"Riley","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why do immune checkpoint inhibitors show limited benefit in unselected prostate cancer patients?","Question",{"text":112,"@type":113},"Immune checkpoint inhibitor monotherapy yields low objective remission rates in unselected cohorts, reflecting an immunologically “cold” phenotype with low baseline T-cell infiltration and weak interferon/antigen-presentation programs.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What does immune heterogeneity explain in prostate cancer beyond the “cold PCa” label?",{"text":117,"@type":113},"Integrated single-cell and spatial studies show substantial differences in immune composition, activation status, and spatial distribution across patients, lesions, and disease stages, including immune-excluded, lymphocyte-rich, and B-cell aggregated regions.",{"name":119,"@type":110,"acceptedAnswer":120},"How can tertiary lymphoid structures (TLS) influence immunotherapy decisions?",{"text":121,"@type":113},"TLS-high regions are described as an actionable “hot minority” resembling inflamed, ICI-responsive cancers, supporting biomarker-guided neoadjuvant approaches or focal immunotherapy.","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},353765,1790198271,{"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":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"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},1374391975076,"https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051","TYPE Mini Review  \nPUBLISHED 12 February 2026 DOI 10.3389/fimmu.2026.1753718  \nOPEN ACCESS  \nEDITED BY  \nYongqiang Zhang,  \nHenan Academy of Innovations in Medical Science, China  \nREVIEWED BY  \nGuo Chengbin,  \nGuangzhou Medical University, China Zihan Xu,  \nThe Rockefeller University, United States  \n*CORRESPONDENCE  \nHaote Chen  \n [chenhaoterobert@126.com](chenhaoterobert@126.com)[ ](chenhaoterobert@126.com)Lin Zhao  \n [lin.zhao@zcmu.edu.cn](lin.zhao@zcmu.edu.cn)[ ](lin.zhao@zcmu.edu.cn)Jingyu Zhu  \n [zjyurology@163.com](zjyurology@163.com)  \n†These authors have contributed equally to this work  \nRECEIVED 25 November 2025  \nREVISED 18 January 2026  \nACCEPTED 21 January 2026  \nPUBLISHED 12 February 2026  \nCITATION  \nZhan M, Zhao B, Wu J, Li K, Chen Y, Chen H, Zhao L and Zhu J (2026) Clinically oriented immune heterogeneity in prostate cancer: emerging targets and strategies.  \nFront. Immunol. 17:1753718 .  \ndoi: 10.3389/fimmu.2026.1753718  \nCOPYRIGHT  \n© 2026 Zhan, Zhao, Wu, Li, Chen, Chen, Zhao and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nClinically oriented immune  \nheterogeneity in prostate cancer: emerging targets and strategies  \nMingWei Zhan 1†, BinBin Zhao 1†, Junjie Wu 2,3†, Kai Li 4†, Yibo Chen 1, Haote Chen 1*, Lin Zhao 1* and Jingyu Zhu 1,2*  \n1 Department of Urology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China, 2 Department of Urology, Hangzhou Integrative Medicine Hospital Affiliated to Zhejiang Chinese Medical University (Hangzhou Red Cross Hospital), Hangzhou, China, 3 Department of Urology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China, 4 Department of Nephrology, Hangzhou Traditional Chinese Medicine (TCM) Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China  \nProstate cancer (PCa) has long been viewed as an immunologically “cold”malignancy because immune checkpoint inhibitors (ICIs) show limited benefit in unselected patients, particularly after progression to metastatic castration-resistant PCa (mCRPC) or treatment-related neuroendocrine PCa (NEPC) . Single-cell and spatial profiling now reveal immune heterogeneity across patients, between lesions, and along the path from localized disease to metastasis. Primary tumors form mosaics of immune-excluded glands, myeloid-suppressed stromal borders, and focal lymphocyte-rich niches with B-cell aggregates and tertiary lymphoid structures (TLS) . TLS-high regions represent an actionable “hot minority” resembling inflamed, ICI-responsive cancers, supporting biomarker-guided neoadjuvant or focal immunotherapy. With dissemination, heterogeneity expands across sites; bone metastases become marrow immune organs dominated by suppressive macrophage/monocyte programs and dysfunctional T cells, often driven by the CCL2–CCR6 axis. Standard therapies remodel these ecosystems, creating inflammatory windows yet fostering adaptive resistance. Mechanistically, myeloiddriven, inflammation-coupled rewiring is central to escape: IL-8/CXCR2 signaling and therapy-induced senescence/SASP recruit and polarize suppressive myeloid cells, reinforcing T-cell exclusion and exhaustion. Variable HLA class I loss and hypoxic or metabolic “functional cold zones” add lesion-specific immune invisibility. Clinically, these insights motivate a heterogeneity-aware framework integrating genomic responder subsets with microenvironmental stratification. Barriermatched strategies include T-cell redirection (PSMA/ST","cbCaiv9PIKlEc71L","https://ap.wps.com/l/cbCaiv9PIKlEc71L","pdf",2219599,"English","# Key themes\n## Immune “cold” prostate cancer and ICI response\n## Immune heterogeneity across patients and lesions\n## Tertiary lymphoid structures and actionable hot minority\n## Metastatic expansion of suppressive programs and axes\n## Therapy-induced ecosystem remodeling and adaptive resistance\n## HLA loss and functional immune cold zones\n## Clinical implications and heterogeneity-aware strategies\n# 1 Introduction\n## Disease burden and immunotherapy challenge","[{\"question\":\"Why do immune checkpoint inhibitors show limited benefit in unselected prostate cancer patients?\",\"answer\":\"Immune checkpoint inhibitor monotherapy yields low objective remission rates in unselected cohorts, reflecting an immunologically “cold” phenotype with low baseline T-cell infiltration and weak interferon/antigen-presentation programs.\"},{\"question\":\"What does immune heterogeneity explain in prostate cancer beyond the “cold PCa” label?\",\"answer\":\"Integrated single-cell and spatial studies show substantial differences in immune composition, activation status, and spatial distribution across patients, lesions, and disease stages, including immune-excluded, lymphocyte-rich, and B-cell aggregated regions.\"},{\"question\":\"How can tertiary lymphoid structures (TLS) influence immunotherapy decisions?\",\"answer\":\"TLS-high regions are described as an actionable “hot minority” resembling inflamed, ICI-responsive cancers, supporting biomarker-guided neoadjuvant approaches or focal immunotherapy.\"}]","Clinically oriented immune heterogeneity in prostate cancer: emerging targets and strategies - Mini Review | PDF",1790107122,25]