MINI REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1614707
This article is part of the Research TopicTargeting tumor-initiating cells to enhance cancer immunotherapy in digestive system tumorsView all 9 articles
Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities
Provisionally accepted
- 1Wenzhou Medical University, Wenzhou, China
- 2School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai Municipality, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by poor prognosis, strong resistance to therapy, and a dense immunosuppressive tumor microenvironment (TME). A small subset of cells known as cancer stem cells (CSCs), or tumor-initiating cells (TICs), are increasingly recognized as key contributors to tumor initiation, metastasis, immune evasion, and treatment failure. These cells are defined by their self-renewal capacity, plasticity, and resistance to chemotherapeutic and targeted therapies. Pancreatic cancer stem cells (PaCSCs) are maintained by specific surface markers (CD44, CD133, EpCAM, ALDH1A1) and regulated by stemness-associated signaling pathways such as Wnt/β-catenin, Notch, Hedgehog, and TGF-β. Their survival is further enhanced by metabolic reprogramming, including shifts between glycolysis and oxidative phosphorylation and the activation of ROS-detoxifying enzymes. Importantly, PaCSCs reside in specialized niches formed by hypoxia, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and extracellular matrix (ECM) components that together shield them from immune clearance and promote therapeutic resistance. This review outlines the molecular features and functional roles of PaCSCs, their interaction with the TME, and recent advances in targeting this CSC-stroma network. Promising therapeutic strategies, such as CAR-T/NK cell therapies, epigenetic inhibitors, and combination regimens with checkpoint blockade or stromal modulators, are discussed in the context of ongoing clinical trials. Targeting both CSCs and their supportive microenvironment is emerging as a necessary strategy to overcome resistance and improve clinical outcomes in PDAC.
Keywords: Pancreatic Ductal Adenocarcinoma, tumor-initiating cell, Cancer stem cell, Tumor Microenvironment, Immune Evasion
Received: 19 Apr 2025; Accepted: 25 Jul 2025.
Copyright: © 2025 Zhou, Li, Lu and Hong. 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) or licensor 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.
* Correspondence: Yanggang Hong, Wenzhou Medical University, Wenzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.