Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities
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 increa...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1614707/full |
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| author | Jun Zhou Jiajun Li Jiajun Li Haoyi Lu Yanggang Hong Yanggang Hong |
| author_facet | Jun Zhou Jiajun Li Jiajun Li Haoyi Lu Yanggang Hong Yanggang Hong |
| author_sort | Jun Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-db9ce12ea36841f08a9bd47b28e6b9ec |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-db9ce12ea36841f08a9bd47b28e6b9ec2025-08-20T03:35:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16147071614707Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunitiesJun Zhou0Jiajun Li1Jiajun Li2Haoyi Lu3Yanggang Hong4Yanggang Hong5Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute and Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute and Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaPancreatic 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1614707/fullpancreatic ductal adenocarcinomatumor-initiating cellcancer stem celltumor microenvironmentimmune evasion |
| spellingShingle | Jun Zhou Jiajun Li Jiajun Li Haoyi Lu Yanggang Hong Yanggang Hong Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities Frontiers in Immunology pancreatic ductal adenocarcinoma tumor-initiating cell cancer stem cell tumor microenvironment immune evasion |
| title | Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities |
| title_full | Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities |
| title_fullStr | Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities |
| title_full_unstemmed | Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities |
| title_short | Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities |
| title_sort | deciphering the secrets of tumor initiating cells in pancreatic ductal adenocarcinoma microenvironment mechanisms and therapeutic opportunities |
| topic | pancreatic ductal adenocarcinoma tumor-initiating cell cancer stem cell tumor microenvironment immune evasion |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1614707/full |
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