{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T01:24:31Z","timestamp":1793582671219,"version":"4.5.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017555","name":"Zhejiang University Student Science and Technology Innovation Activity Plan","doi-asserted-by":"publisher","award":["2025R413A025"],"award-info":[{"award-number":["2025R413A025"]}],"id":[{"id":"10.13039\/501100017555","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\/\u03b2-catenin, Notch, Hedgehog, and TGF-\u03b2. 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.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1614707","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T05:35:13Z","timestamp":1755063313000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities"],"prefix":"10.3389","volume":"16","author":[{"given":"Jun","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanggang","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.13027","article-title":"Pancreatic cancer: A review","volume":"326","author":"Park","year":"2021","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3322\/caac.21871","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA: Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1053\/j.gastro.2022.03.056","article-title":"Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment","volume":"163","author":"Wood","year":"2022","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41575-023-00840-w","article-title":"Therapeutic developments in pancreatic cancer","volume":"21","author":"Hu","year":"2024","journal-title":"Nat Rev Gastroenterol hepatol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s12943-025-02265-2","article-title":"Cancer stem cells and niches: challenges in immunotherapy resistance","volume":"24","author":"Pan","year":"2025","journal-title":"Mol cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.06.003","article-title":"Cancer stem cell mimicry for immune evasion and therapeutic resistance","volume":"31","author":"Saw","year":"2024","journal-title":"Cell Stem Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2064","DOI":"10.1016\/j.ccell.2024.10.008","article-title":"Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy","volume":"42","author":"Yang","year":"2024","journal-title":"Cancer Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24573","article-title":"CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells","volume":"125","author":"Hong","year":"2009","journal-title":"Int J cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-2030","article-title":"Identification of pancreatic cancer stem cells","volume":"67","author":"Li","year":"2007","journal-title":"Cancer Res"},{"key":"B10","article-title":"Detection of tumor stem cell markers in pancreatic carcinoma cell lines","volume":"6","author":"Olempska","year":"2007","journal-title":"Hepatobiliary pancreatic Dis international: HBPD Int"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.02.015","article-title":"The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells","volume":"16","author":"Plaks","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.semcancer.2010.03.004","article-title":"Cancer stem cells in solid tumors","volume":"20","author":"Hermann","year":"2010","journal-title":"Semin Cancer Biol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1186\/s13045-020-00958-3","article-title":"Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma","volume":"13","author":"Qian","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1007\/s10555-021-09979-x","article-title":"The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance","volume":"40","author":"Patil","year":"2021","journal-title":"Cancer metastasis Rev"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046391","article-title":"Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential","volume":"7","author":"Salnikov","year":"2012","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/1475-2867-13-62","article-title":"Increased invasion and tumorigenicity capacity of CD44+\/CD24- breast cancer MCF7 cells in vitro and in nude mice","volume":"13","author":"Yan","year":"2013","journal-title":"Cancer Cell Int"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-323014","article-title":"Exosome-delivered CD44v6\/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment","volume":"71","author":"Xie","year":"2022","journal-title":"Gut"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.532887","article-title":"Pancreatic cancer stem-like cells display aggressive behavior mediated via activation of FoxQ1","volume":"289","author":"Bao","year":"2014","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","first-page":"7331","DOI":"10.3390\/ijms24087331","article-title":"Identification and clinical significance of pancreatic cancer stem cells and their chemotherapeutic drug resistance","volume":"24","author":"Kuo","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2012.1516","article-title":"Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells","volume":"41","author":"Duong","year":"2012","journal-title":"Int J Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.canlet.2012.03.018","article-title":"Pancreatic cancer stem cells: emerging target for designing novel therapy","volume":"338","author":"Li","year":"2013","journal-title":"Cancer letters"},{"key":"B22","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1186\/s13046-016-0406-z","article-title":"PIM-1 contributes to the Malignancy of pancreatic cancer and displays diagnostic and prognostic value","volume":"35","author":"Xu","year":"2016","journal-title":"J Exp Clin Cancer research: CR"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1289-1","article-title":"TGF-\u03b21 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation","volume":"39","author":"Cave","year":"2020","journal-title":"Oncogene"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33947","article-title":"HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties","volume":"7","author":"Abel","year":"2018","journal-title":"eLife"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0146564","article-title":"Dominant expression of DCLK1 in human pancreatic cancer stem cells accelerates tumor invasion and metastasis","volume":"11","author":"Ito","year":"2016","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1186\/s13046-022-02516-w","article-title":"LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer","volume":"41","author":"Cave","year":"2022","journal-title":"J Exp Clin Cancer research: CR"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2022.10.006","article-title":"Calcium channel \u03b12\u03b41 is essential for pancreatic tumor-initiating cells through sequential phosphorylation of PKM2","volume":"15","author":"Liu","year":"2023","journal-title":"Cell Mol Gastroenterol hepatol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"4242","DOI":"10.3390\/ijms20174242","article-title":"Wnt\/\u03b2-catenin signaling: the culprit in pancreatic carcinogenesis and therapeutic resistance","volume":"20","author":"Ram Makena","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"7030","DOI":"10.3390\/ijms24087030","article-title":"Cancer stem cells in pancreatic ductal adenocarcinoma","volume":"24","author":"Bubin","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2017.4129","article-title":"Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)","volume":"51","author":"Katoh","year":"2017","journal-title":"Int J Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.58612","article-title":"Wnt\/\u03b2-catenin Signaling Inhibitors suppress the Tumor-initiating properties of a CD44(+)CD133(+) subpopulation of Caco-2 cells","volume":"17","author":"Kim","year":"2021","journal-title":"Int J Biol Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1053\/j.gastro.2009.01.008","article-title":"Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma","volume":"136","author":"Plentz","year":"2009","journal-title":"Gastroenterology"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091983","article-title":"The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer","volume":"9","author":"Abel","year":"2014","journal-title":"PLoS One"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1446","article-title":"Notch1 and notch2 have opposite effects on embryonal brain tumor growth","volume":"64","author":"Fan","year":"2004","journal-title":"Cancer Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0858","article-title":"Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors","volume":"66","author":"Fan","year":"2006","journal-title":"Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2004.10.062","article-title":"A novel series of potent gamma-secretase inhibitors based on a benzobicyclo[4.2.1]nonane core","volume":"15","author":"Lewis","year":"2005","journal-title":"Bioorganic medicinal Chem Lett"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature02009","article-title":"Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis","volume":"425","author":"Thayer","year":"2003","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1411679111","article-title":"Stromal response to Hedgehog signaling restrains pancreatic cancer progression","volume":"111","author":"Lee","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B39","doi-asserted-by":"publisher","first-page":"269","DOI":"10.31083\/j.fbl2907269","article-title":"Knockdown of TGF-\u03b2 in pancreatic cancer helps ameliorate gemcitabine resistance","volume":"29","author":"Wang","year":"2024","journal-title":"Front bioscience (Landmark edition)"},{"key":"B40","first-page":"799","article-title":"Transforming growth factor beta receptor I inhibitor sensitizes drug-resistant pancreatic cancer cells to gemcitabine","volume":"32","author":"Kim","year":"2012","journal-title":"Anticancer Res"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-2213","article-title":"Metabolic reprogramming is an initial step in pancreatic carcinogenesis that can be targeted to inhibit acinar-to-ductal metaplasia","volume":"84","author":"Neu\u00df","year":"2024","journal-title":"Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01518-2","article-title":"Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma","volume":"40","author":"Nimmakayala","year":"2021","journal-title":"Oncogene"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.02.008","article-title":"The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment","volume":"11","author":"Zhang","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.3390\/metabo13111132","article-title":"Transcriptome and lipidomic analysis suggests lipid metabolism reprogramming and upregulating SPHK1 promotes stemness in pancreatic ductal adenocarcinoma stem-like cells","volume":"13","author":"Xu","year":"2023","journal-title":"Metabolites"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2174\/0115680096357993241206072609","article-title":"Targeting glutamine metabolic reprogramming in pancreatic cancer: current insights and future directions","volume":"25","author":"Ma","year":"2025","journal-title":"Curr Cancer Drug Targets"},{"key":"B46","doi-asserted-by":"publisher","first-page":"216649","DOI":"10.1016\/j.canlet.2024.216649","article-title":"Crosstalk between metabolic remodeling and epigenetic reprogramming: A new perspective on pancreatic cancer","volume":"587","author":"Ren","year":"2024","journal-title":"Cancer letters"},{"key":"B47","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.canlet.2016.08.023","article-title":"Gemcitabine treatment promotes pancreatic cancer stemness through the Nox\/ROS\/NF-\u03baB\/STAT3 signaling cascade","volume":"382","author":"Zhang","year":"2016","journal-title":"Cancer letters"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-3112","article-title":"Heterogeneity and targeting of pancreatic cancer stem cells","volume":"18","author":"Penchev","year":"2012","journal-title":"Clin Cancer Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"798","DOI":"10.3892\/ijo.2011.1254","article-title":"Intrinsic gemcitabine resistance in a novel pancreatic cancer cell line is associated with cancer stem cell-like phenotype","volume":"40","author":"Hu","year":"2012","journal-title":"Int J Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2018.29","article-title":"Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges","volume":"15","author":"Fukumura","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"4765","DOI":"10.3390\/ijms22094765","article-title":"Pancreatic cancer and therapy: role and regulation of cancer stem cells","volume":"22","author":"Barman","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01280","article-title":"Cancer stem cells-origins and biomarkers: perspectives for targeted personalized therapies","volume":"11","author":"Walcher","year":"2020","journal-title":"Front Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.tips.2023.11.006","article-title":"Biomarkers and targeted therapy for cancer stem cells","volume":"45","author":"Liu","year":"2024","journal-title":"Trends Pharmacol Sci"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.7150\/thno.41648","article-title":"Stem cell programs in cancer initiation, progression, and therapy resistance","volume":"10","author":"Huang","year":"2020","journal-title":"Theranostics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41392-020-0110-5","article-title":"Targeting cancer stem cell pathways for cancer therapy","volume":"5","author":"Yang","year":"2020","journal-title":"Signal transduction targeted Ther"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1097\/MPA.0000000000001828","article-title":"Hypoxia promotes pancreatic cancer cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential by the HIF-1\u03b1\/notch signaling pathway","volume":"50","author":"Mu","year":"2021","journal-title":"Pancreas"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1159\/000325538","article-title":"Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1\u03b1-dependent manner in pancreatic cancer cells","volume":"78","author":"Hashimoto","year":"2011","journal-title":"Pathobiology"},{"key":"B58","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/1475-2867-13-119","article-title":"Role of the Hypoxia-inducible factor-1 alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells","volume":"13","author":"Zhu","year":"2013","journal-title":"Cancer Cell Int"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.3390\/ijms17071025","article-title":"CD133 modulate HIF-1\u03b1 Expression under hypoxia in EMT phenotype pancreatic cancer stem-like cells","volume":"17","author":"Maeda","year":"2016","journal-title":"Int J Mol Sci"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.7150\/jca.81320","article-title":"Hypoxia-elicited exosomes promote the chemoresistance of pancreatic cancer cells by transferring LncROR via hippo signaling","volume":"14","author":"Wang","year":"2023","journal-title":"J Cancer"},{"key":"B61","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s11658-018-0078-0","article-title":"STAT3, stem cells, cancer stem cells and p63","volume":"23","author":"Galoczova","year":"2018","journal-title":"Cell Mol Biol letters"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205260","article-title":"Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis","volume":"21","author":"Niu","year":"2002","journal-title":"Oncogene"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206122","article-title":"Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis","volume":"22","author":"Wei","year":"2003","journal-title":"Oncogene"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-018-0493-6","article-title":"Mast cells and angiogenesis in pancreatic ductal adenocarcinoma","volume":"18","author":"Longo","year":"2018","journal-title":"Clin Exp Med"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.06.005","article-title":"Macrophage-expressed CD51 promotes cancer stem cell properties via the TGF-\u03b21\/smad2\/3 axis in pancreatic cancer","volume":"459","author":"Zhang","year":"2019","journal-title":"Cancer letters"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-021-09597-x","article-title":"microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3","volume":"38","author":"Chang","year":"2022","journal-title":"Cell Biol toxicol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2017-5667","article-title":"Abstract 5667: Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance","volume":"77","author":"D\u2019Errico","year":"2017","journal-title":"Cancer Res"},{"key":"B68","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1158\/2767-9764.CRC-24-0491","article-title":"Targeting pancreatic cancer cell stemness by blocking fibronectin-binding integrins on cancer-associated fibroblasts","volume":"5","author":"Wu","year":"2025","journal-title":"Cancer Res Commun"},{"key":"B69","doi-asserted-by":"publisher","first-page":"3998","DOI":"10.3390\/cancers14163998","article-title":"The extracellular matrix: A key accomplice of cancer stem cell migration, metastasis formation, and drug resistance in PDAC","volume":"14","author":"Wang","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1152312","article-title":"Pancreatic cancer and fibrosis: Targeting metabolic reprogramming and crosstalk of cancer-associated fibroblasts in the tumor microenvironment","volume":"14","author":"Li","year":"2023","journal-title":"Front Immunol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1186\/s12943-023-01876-x","article-title":"Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment","volume":"22","author":"Ma","year":"2023","journal-title":"Mol cancer"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00197.2005","article-title":"Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase","volume":"289","author":"Edderkaoui","year":"2005","journal-title":"Am J Physiol Gastrointestinal liver Physiol"},{"key":"B73","doi-asserted-by":"publisher","first-page":"6619","DOI":"10.1038\/s41467-022-34395-2","article-title":"Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment","volume":"13","author":"Luo","year":"2022","journal-title":"Nat Commun"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1516","article-title":"The molecular classification of cancer-associated fibroblasts on a pan-cancer single-cell transcriptional atlas","volume":"13","author":"Chen","year":"2023","journal-title":"Clin Trans Med"},{"key":"B75","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12943-024-02191-9","article-title":"Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response","volume":"24","author":"Jenkins","year":"2025","journal-title":"Mol cancer"},{"key":"B76","doi-asserted-by":"publisher","first-page":"154465","DOI":"10.1016\/j.prp.2023.154465","article-title":"A comprehensive survey into the role of exosomes in pancreatic cancer; from the origin of cancer to the progress and possibility of diagnosis and treatment","volume":"245","author":"Farahmand","year":"2023","journal-title":"Pathol Res practice"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2016-3955","article-title":"Abstract 3955: Expression of cancer stem cell-associated proteins in exosomes derived from ascites of patients with advanced pancreatic cancer","volume":"76","author":"Sakaue","year":"2016","journal-title":"Cancer Res"},{"key":"B78","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.canlet.2021.04.030","article-title":"Exosomal circ_0030167 derived from BM-MSCs inhibits the invasion, migration, proliferation and stemness of pancreatic cancer cells by sponging miR-338-5p and targeting the Wif1\/Wnt8\/\u03b2-catenin axis","volume":"512","author":"Yao","year":"2021","journal-title":"Cancer letters"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31089","article-title":"Role of stem cell derived exosomes in tumor biology","volume":"142","author":"Sharma","year":"2018","journal-title":"Int J cancer"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.12274","article-title":"Hypoxic cancer cells-derived exosomes strengthen the development of cancer stem cell-like properties through delivering LINC00665 in thyroid cancer cells","volume":"49","author":"Zhou","year":"2025","journal-title":"Cell Biol Int"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2711","article-title":"Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts","volume":"6","author":"Chowdhury","year":"2015","journal-title":"Oncotarget"},{"key":"B82","doi-asserted-by":"publisher","first-page":"9133658","DOI":"10.1155\/2022\/9133658","article-title":"The role of cancer stem cell-derived exosomes in cancer progression","volume":"2022","author":"Li","year":"2022","journal-title":"Stem Cells Int"},{"key":"B83","doi-asserted-by":"publisher","first-page":"1325860","DOI":"10.3389\/fimmu.2024.1325860","article-title":"Complete remission of advanced pancreatic cancer induced by claudin18","volume":"15","author":"Zhong","year":"2024","journal-title":"2-targeted CAR-T Cell therapy: Case Rep Front Immunol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.168","article-title":"Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy","volume":"28","author":"Klapdor","year":"2017","journal-title":"Hum Gene Ther"},{"key":"B85","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1186\/s13046-021-02070-x","article-title":"PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models","volume":"40","author":"Morosi","year":"2021","journal-title":"J Exp Clin Cancer research: CR"},{"key":"B86","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1186\/s40425-019-0667-0","article-title":"Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape","volume":"7","author":"Osipov","year":"2019","journal-title":"J immunother cancer"},{"key":"B87","doi-asserted-by":"publisher","first-page":"105485","DOI":"10.1016\/j.jbc.2023.105485","article-title":"Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions","volume":"300","author":"WMF","year":"2024","journal-title":"J Biol Chem"},{"key":"B88","doi-asserted-by":"publisher","first-page":"106767","DOI":"10.1016\/j.ejps.2024.106767","article-title":"Bifunctional HDAC and DNMT inhibitor induces viral mimicry activates the innate immune response in triple-negative breast cancer","volume":"197","author":"Fan","year":"2024","journal-title":"Eur J Pharm Sci"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604437","article-title":"CD133\/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers","volume":"99","author":"Smith","year":"2008","journal-title":"Br J cancer"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2016-1481","article-title":"Abstract 1481: Preclinical validation of a novel CD133\/CD3 bispecific T-cell engager (BiTE) antibody to target patient-derived glioblastoma cells","volume":"76","author":"Vora","year":"2016","journal-title":"Cancer Res"},{"key":"B91","doi-asserted-by":"publisher","first-page":"23","DOI":"10.22088\/IJMCM.BUMS.10.1.23","article-title":"DCLK1 inhibition sensitizes colorectal cancer cells to radiation treatment","volume":"10","author":"Mohammadi","year":"2021","journal-title":"Int J Mol Cell Med"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.05.045","article-title":"CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells","volume":"138","author":"Majeti","year":"2009","journal-title":"Cell"},{"key":"B93","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1186\/s13045-021-01163-6","article-title":"SIRP\u03b1-\u03b1CD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells","volume":"14","author":"Tahk","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/nature03319","article-title":"Wnt signalling in stem cells and cancer","volume":"434","author":"Reya","year":"2005","journal-title":"Nature"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01625-x","article-title":"Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication","volume":"28","author":"Theruvath","year":"2022","journal-title":"Nat Med"},{"key":"B96","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.jhep.2023.10.006","article-title":"Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma","volume":"80","author":"Zhang","year":"2024","journal-title":"J hepatol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0002","article-title":"The interplay between extracellular matrix remodeling and cancer therapeutics","volume":"14","author":"Prakash","year":"2024","journal-title":"Cancer discov"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2686","article-title":"MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy","volume":"77","author":"Beloueche-Babari","year":"2017","journal-title":"Cancer Res"},{"key":"B99","doi-asserted-by":"publisher","first-page":"6043","DOI":"10.1038\/s41467-024-50450-6","article-title":"Necroptosis enhances \u2018don\u2019t eat me\u2019 signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis","volume":"15","author":"Liao","year":"2024","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1614707\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T05:35:15Z","timestamp":1755063315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1614707\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":99,"alternative-id":["10.3389\/fimmu.2025.1614707"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1614707","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]},"article-number":"1614707"}}