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The review discusses how distinct PDAC subtypes shape microenvironment features and how cancer cells domesticate stromal components to act as progression collaborators. It analyzes mechanisms underlying immunosuppressive TME formation, emphasizing inflammation, intrinsic genetic alterations, metabolic reprogramming regulation, CAF roles, and immune-cell contributions to metastasis. Soluble molecules and exosomes are highlighted for PDAC progression and immune evasion, and novel interaction-focused therapeutic strategies are proposed for future precision interventions.",{"@graph":69,"@context":123},[70,84,106],{"@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/domestication-and-feedback-bidirectional-hijacking-in-pancreatic-ductal-adenocarcinoma-microenvironment/373646/",{"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/domestication-and-feedback-bidirectional-hijacking-in-pancreatic-ductal-adenocarcinoma-microenvironment/373646.png","ImageObject",300,407,{"name":92,"@type":93},"Mabel","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What components make up the pancreatic ductal adenocarcinoma tumor microenvironment (TME)?","Question",{"text":113,"@type":114},"The PDAC TME includes extracellular matrix, cancer-associated fibroblasts (CAFs), vasculature, neural elements, and immune cell populations that collectively shape tumor behavior.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does the TME contribute to therapy resistance and immune evasion in PDAC?",{"text":118,"@type":114},"A desmoplastic stromal network supports proliferation, invasion, metastasis, and resistance to immunotherapy and chemotherapy while generating a profoundly immunosuppressive “cold” immune environment that impairs immune surveillance.",{"name":120,"@type":111,"acceptedAnswer":121},"Which mechanisms are emphasized for forming the immunosuppressive microenvironment?",{"text":122,"@type":114},"The review highlights inflammation and intrinsic genetic alterations, regulatory effects of metabolic reprogramming, contributions of CAFs, and roles of immune cells in cancer cell metastasis.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},373646,1790470730,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},7971474920318,"https://ap-avatar.wpscdn.com/avatar/74000ee537e6b0ca360?x-image-process=image/resize,m_fixed,w_180,h_180&k=1788430171632181674","TYPE Review  \nPUBLISHED 11 August 2025  \nDOI 10.3389/fimmu.2025.1585858  \nOPEN ACCESS  \nEDITED BY  \nWei Zhao,  \nShandong University, China  \nREVIEWED BY  \nHadida Yasmin,  \nCooch Behar Panchanan Barma University, India  \nNabanita Chatterjee,  \nThe Ohio State University, United States  \n*CORRESPONDENCE  \nQian Dong  \n [dongqian08@163.com](dongqian08@163.com)  \nRECEIVED 31 March 2025  \nACCEPTED 14 July 2025  \nPUBLISHED 11 August 2025  \nCITATION  \nQiao Y, Yin H, Zhang Y, Zhang J and Dong Q (2025) Domestication and feedback:  \nbidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment.  \nFront. Immunol. 16:1585858 .  \ndoi: 10.3389/fimmu.2025.1585858  \nCOPYRIGHT  \n© 2025 Qiao, Yin, Zhang, Zhang and Dong.  \nThis 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.  \nDomestication and feedback: bidirectional hijacking in pancreatic ductaladenocarcinoma microenvironment  \nYuxi Qiao 1, Haobo Yin 1, Yong Zhang 2, Jingdong Zhang 3 and Qian Dong 3*  \n1 Medical Oncology Department of Gastrointestinal Tumors, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China, 2 Pathology Department, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Shenyang, China, 3 Medical Oncology Department of Gastrointestinal Tumors, Liaoning Cancer Hospital and Institute, Liaoning Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Shenyang, China  \nPancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor microenvironment (TME) composed of a dense extracellular matrix, cancerassociated fibroblasts (CAFs), vasculature, neural elements, and immune cell populations. This complex network promotes tumor proliferation, invasion, metastasis, and resistance to immunotherapy and chemotherapy. The microenvironmental characteristics of the various PDAC subtypes are discussed in this review. And we examines the role of cancer cells in the TME, highlighting their ability to manipulate stromal components to serve as collaborators in tumor progression. Furthermore, we explored the formation mechanism of the immunosuppressive microenvironment in PDAC, paying attention on Inflammation and intrinsic genetic alterations, the regulatory effect of metabolic reprogramming, the contribution of CAFs and the role of immune cells in cancer cell metastasis. This review shows the role of soluble molecules and exosomes in facilitating PDAC progression and immune evasion within the microenvironment. In conclusion, we outline the novel therapeutic strategies that focus on the interaction between cancer cells and their microenvironment, with the objective of offering new insights for future precision medical interventions.  \nKEYWORDS  \npancreatic ductal adenocarcinoma, tumor microenvironment, cancer-associated fibroblasts, combination therapy, extracellular matrix  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \n1 Introduction  \nPancreatic ductal adenocarcinoma (PDAC) is among the most lethal gastrointestinal malignancies, with an estimated five-year survival rate of 13%(1) . According to the latest cancer statistics, it is the third leading cause of cancer-related deaths (1) . By 2040, it is projected to rank as the second leading cause of cancer-related mortality globally (2) . The mainstay of treatment for patients with resectable and borderline resectable PDAC with the goal of increasing R0 resection rates is surgery, supplemen","cbCaiiFSHNzALEvg","https://ap.wps.com/l/cbCaiiFSHNzALEvg","pdf",1277109,23,"English","# Introduction\n## PDAC burden and treatment challenges\n## Tumor microenvironment as a barrier to therapy\n# Tumor microenvironment composition and dynamics\n## CAFs, immune subsets, ECM, vasculature, and neural elements\n## Desmoplastic stroma, perineural invasion, hypoperfusion, immunosuppression","[{\"question\":\"What components make up the pancreatic ductal adenocarcinoma tumor microenvironment (TME)?\",\"answer\":\"The PDAC TME includes extracellular matrix, cancer-associated fibroblasts (CAFs), vasculature, neural elements, and immune cell populations that collectively shape tumor behavior.\"},{\"question\":\"How does the TME contribute to therapy resistance and immune evasion in PDAC?\",\"answer\":\"A desmoplastic stromal network supports proliferation, invasion, metastasis, and resistance to immunotherapy and chemotherapy while generating a profoundly immunosuppressive “cold” immune environment that impairs immune surveillance.\"},{\"question\":\"Which mechanisms are emphasized for forming the immunosuppressive microenvironment?\",\"answer\":\"The review highlights inflammation and intrinsic genetic alterations, regulatory effects of metabolic reprogramming, contributions of CAFs, and roles of immune cells in cancer cell metastasis.\"}]","Domestication and feedback - bidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment | PDF",1790200115,58]