Domestication and feedback - bidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment

Sep 23, 2026

Uploaded by Mabel

Pancreatic ductal adenocarcinoma (PDAC) is reviewed as a disease driven by a dense, multifactor tumor microenvironment (TME) containing extracellular matrix, cancer-associated fibroblasts (CAFs), vasculature, neural elements, and immune populations. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Introduction

PDAC burden and treatment challenges

Tumor microenvironment as a barrier to therapy

Tumor microenvironment composition and dynamics

CAFs, immune subsets, ECM, vasculature, and neural elements

Desmoplastic stroma, perineural invasion, hypoperfusion, immunosuppression

TYPE Review PUBLISHED 11 August 2025 DOI 10.3389/fimmu.2025.1585858 OPEN ACCESS EDITED BY Wei Zhao, Shandong University, China REVIEWED BY Hadida Yasmin, Cooch Behar Panchanan Barma University, India Nabanita Chatterjee, The Ohio State University, United States *CORRESPONDENCE Qian Dong [dongqian08@163.com](dongqian08@163.com) RECEIVED 31 March 2025 ACCEPTED 14 July 2025 PUBLISHED 11 August 2025 CITATION Qiao Y, Yin H, Zhang Y, Zhang J and Dong Q (2025) Domestication and feedback: bidirectional hijacking in pancreatic ductal adenocarcinoma microenvironment. Front. Immunol. 16:1585858 . doi: 10.3389/fimmu.2025.1585858 COPYRIGHT © 2025 Qiao, Yin, Zhang, Zhang and Dong. 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. Domestication and feedback: bidirectional hijacking in pancreatic ductaladenocarcinoma microenvironment Yuxi Qiao 1, Haobo Yin 1, Yong Zhang 2, Jingdong Zhang 3 and Qian Dong 3* 1 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 Pancreatic 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. KEYWORDS pancreatic ductal adenocarcinoma, tumor microenvironment, cancer-associated ﬁbroblasts, combination therapy, extracellular matrix Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) 1 Introduction Pancreatic 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

FAQs

What components make up the pancreatic ductal adenocarcinoma tumor microenvironment (TME)?

The PDAC TME includes extracellular matrix, cancer-associated fibroblasts (CAFs), vasculature, neural elements, and immune cell populations that collectively shape tumor behavior.

How does the TME contribute to therapy resistance and immune evasion in PDAC?

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.

Which mechanisms are emphasized for forming the immunosuppressive microenvironment?

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.

Sep 23, 2026

Uploaded by Mabel