{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:07:16Z","timestamp":1789189636043,"version":"build-2803163510"},"reference-count":112,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["RC2026"],"award-info":[{"award-number":["RC2026"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RC2026"],"award-info":[{"award-number":["RC2026"]}],"id":[{"id":"https:\/\/ror.org\/00789fa95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, partly because its dense, heterogeneous stroma restricts drug delivery, promotes immune exclusion, and supports therapeutic resistance. Stromal targeting has, therefore, evolved from broad depletion towards biomarker-guided reprogramming and normalization strategies that aim to restore vascular function, improve intratumoral drug penetration, and enhance antitumor immunity. This review summarizes evidence on stromal biomarkers with prognostic or predictive value, including tumor\u2013stroma ratio, fibrosis burden, cancer-associated fibroblast states, extracellular matrix stiffness, vascular accessibility, and spatial immune features. It also examines emerging therapeutic approaches to reprogram the PDAC stroma, such as repurposed drugs, immune\u2013stromal modulators, metabolic interventions, and advanced delivery systems. Emphasis is placed on clinically or translationally supported strategies, including CXCR4, CD40, CD73, vitamin D receptor agonism, matrix remodeling, and biomarker-driven stratification. Overall, PDAC stroma is a dynamic therapeutic target, requiring composite biomarkers and rational combinations with chemotherapy, immunotherapy, and delivery-enhancing strategies.<\/jats:p>","DOI":"10.3390\/cells15181637","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T08:07:41Z","timestamp":1789027661000},"page":"1637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomarker-Driven Strategies for Stromal Reprogramming in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7827-7742","authenticated-orcid":false,"given":"Maria","family":"De Luca","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS de Bellis, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8853-3533","authenticated-orcid":false,"given":"Francesco","family":"Balestra","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS de Bellis, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Panzetta","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS de Bellis, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-8060","authenticated-orcid":false,"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[{"name":"Scientific Direction, National Institute of Gastroenterology IRCCS de Bellis, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0812-4441","authenticated-orcid":false,"given":"Maria Principia","family":"Scavo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS de Bellis, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","unstructured":"(2026, June 10). Pancreatic Cancer\u2014Cancer Stat Facts, Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/pancreas.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"282","DOI":"10.62347\/TXSZ9359","article-title":"Second-Line Nab-Paclitaxel and Gemcitabine for Advanced Pancreatic Cancer Following FOLFIRINOX: Outcomes and Insights","volume":"16","author":"Kostek","year":"2026","journal-title":"Am. J. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19396","DOI":"10.18632\/oncotarget.25036","article-title":"Advanced Pancreatic Cancer: A Meta-Analysis of Clinical Trials over Thirty Years","volume":"9","author":"Hall","year":"2018","journal-title":"Oncotarget"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"McCarthy, J.B., El-Ashry, D., and Turley, E.A. (2018). Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression. Front. Cell Dev. Biol., 6.","DOI":"10.3389\/fcell.2018.00048"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, Z., Yang, Q., Tan, Y., Tang, Y., Ye, J., Yuan, B., and Yu, W. (2021). Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.613534"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"pgad405","DOI":"10.1093\/pnasnexus\/pgad405","article-title":"Stiffness-Induced Cancer-Associated Fibroblasts Are Responsible for Immunosuppression in a Platelet-Derived Growth Factor Ligand-Dependent Manner","volume":"2","author":"Gamradt","year":"2023","journal-title":"PNAS Nexus"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ccr.2012.01.007","article-title":"Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma","volume":"21","author":"Provenzano","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1974233","DOI":"10.1080\/2162402X.2021.1974233","article-title":"Tumor Hypoxia: An Important Regulator of Tumor Progression or a Potential Modulator of Tumor Immunogenicity?","volume":"10","author":"Terry","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4980","DOI":"10.7150\/thno.73222","article-title":"Single-Cell Profiling of Microenvironment Components by Spatial Localization in Pancreatic Ductal Adenocarcinoma","volume":"12","author":"Han","year":"2022","journal-title":"Theranostics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100188","DOI":"10.1016\/j.adcanc.2026.100188","article-title":"Reprogramming the Pancreatic Tumor Microenvironment Using Smart Stem Cells: A New Frontier in Cancer Therapy","volume":"17","author":"Khan","year":"2026","journal-title":"Adv. Cancer Biol. Metastasis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3390\/biologics3040022","article-title":"Targeting Hyaluronan Synthesis in Cancer: A Road Less Travelled","volume":"3","author":"Karalis","year":"2023","journal-title":"Biologics"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Barbazan, J., P\u00e9rez-Gonz\u00e1lez, C., G\u00f3mez-Gonz\u00e1lez, M., Dedenon, M., Richon, S., Latorre, E., Serra, M., Mariani, P., Descroix, S., and Sens, P. (2021). Cancer-Associated Fibroblasts Actively Compress Cancer Cells and Modulate Mechanotransduction. bioRxiv.","DOI":"10.1101\/2021.04.05.438443"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1016\/j.cell.2026.02.019","article-title":"Proteostasis Sustains T Cell Differentiation Potential and Tumor-Infiltrating Lymphocyte Function","volume":"189","author":"Ge","year":"2026","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Anand, N., Peh, K.H., and Kolesar, J.M. (2023). Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032858"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wu, S., Anand, N., Guo, Z., Li, M., Santiago Figueroa, M., Jung, L., Kelly, S., and Franses, J.W. (2025). Bridging Immune Evasion and Vascular Dynamics for Novel Therapeutic Frontiers in Hepatocellular Carcinoma. Cancers, 17.","DOI":"10.3390\/cancers17111860"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Malik, S., Westcott, J.M., Brekken, R.A., and Burrows, F.J. (2021). CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target. Cancers, 14.","DOI":"10.3390\/cancers14010086"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Tiwary, K., Lahusen, A., Inaas, S., Beitzinger, B., Schmid, R., Harms, M., Hauff, S., Arnold, F., Walter, K., and Alcala, S. (2025). Novel Peptide Targeting CXCR4 Disrupt Tumor-Stroma Crosstalk to Eliminate Migrating Cancer Stem Cells. bioRxiv.","DOI":"10.1101\/2025.03.03.641126"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2206335","DOI":"10.1002\/advs.202206335","article-title":"CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism","volume":"10","author":"Liu","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bakleh, M.Z., and Al Haj Zen, A. (2025). The Distinct Role of HIF-1\u03b1 and HIF-2\u03b1 in Hypoxia and Angiogenesis. Cells, 14.","DOI":"10.3390\/cells14090673"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12575-024-00254-1","article-title":"Metabolic and Immunological Implications of MME+CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities","volume":"26","author":"Wang","year":"2024","journal-title":"Biol. Proced. Online"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1136\/gutjnl-2023-329807","article-title":"Axon Guidance Cue SEMA3A Promotes the Aggressive Phenotype of Basal-like PDAC","volume":"73","author":"Lupo","year":"2024","journal-title":"Gut"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/path.5926","article-title":"Cancer-Associated Fibroblasts in Pancreatic Cancer: New Subtypes, New Markers, New Targets","volume":"257","author":"Menezes","year":"2022","journal-title":"J. Pathol."},{"key":"ref_23","first-page":"3417","article-title":"Pancreatic Cancer Cell-Derived Semaphorin 3A Promotes Neuron Recruitment to Accelerate Tumor Growth and Dissemination","volume":"13","author":"Hung","year":"2023","journal-title":"Am. J. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1007\/s12672-026-04808-5","article-title":"Construction of a SEMA3 Family-Based Model to Predict Prognosis and Molecular Subtypes in Pancreatic Ductal Adenocarcinoma","volume":"17","author":"Jin","year":"2026","journal-title":"Discov. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ccell.2025.12.009","article-title":"Spatial Omics at the Forefront: Emerging Technologies, Analytical Innovations, and Clinical Applications","volume":"44","author":"Liu","year":"2026","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.matbio.2020.05.001","article-title":"Fibroblast Heterogeneity and Its Impact on Extracellular Matrix and Immune Landscape Remodeling in Cancer","volume":"91\u201392","author":"Yamauchi","year":"2020","journal-title":"Matrix Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76197","DOI":"10.18632\/oncotarget.12772","article-title":"Highly Aligned Stromal Collagen Is a Negative Prognostic Factor Following Pancreatic Ductal Adenocarcinoma Resection","volume":"7","author":"Drifka","year":"2016","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Spiers, L., Gray, M., Lyon, P., Sivakumar, S., Bekkali, N., Scott, S., Collins, L., Carlisle, R., Wu, F., and Middleton, M. (2023). Clinical Trial Protocol for PanDox: A Phase I Study of Targeted Chemotherapy Delivery to Non-Resectable Primary Pancreatic Tumours Using Thermosensitive Liposomal Doxorubicin (ThermoDox\u00ae) and Focused Ultrasound. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-11228-z"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1097\/JS9.0000000000002059","article-title":"Development and Validation of a CT-Based Radiomics Model to Predict Survival-Graded Fibrosis in Pancreatic Ductal Adenocarcinoma","volume":"111","author":"Shi","year":"2025","journal-title":"Int. J. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kocher, H.M., Georgescu, R., Kotriwala, N., Lawrence, C., Priyadarshini, G., Ackermann, C., Chelala, C., Imrali, A., Hughes, C., and Roberts, R. (2025). Study Protocol: Multi-Centre, Randomised Controlled Clinical Trial Exploring Stromal Targeting in Locally Advanced Pancreatic Cancer; STARPAC2. BMC Cancer, 25.","DOI":"10.1186\/s12885-024-13333-z"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2543614","DOI":"10.1080\/2162402X.2025.2543614","article-title":"A Phase 2 Trial of CXCR4 Antagonism and PD1 Inhibition in Metastatic Pancreatic Adenocarcinoma Reveals Recruitment of T Cells but Also Immunosuppressive Macrophages","volume":"14","author":"Bever","year":"2025","journal-title":"Oncoimmunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1038\/s41591-026-04283-z","article-title":"Quemliclustat and Chemotherapy with or without Zimberelimab in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase 1 Trial","volume":"32","author":"Wainberg","year":"2026","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103895","DOI":"10.1016\/j.redox.2025.103895","article-title":"Phase IB Trial of High Dose Ascorbic Acid + Nab-Paclitaxel + Cisplatin + Gemcitabine in Patients with Untreated Metastatic Pancreatic Cancer","volume":"88","author":"Jameson","year":"2025","journal-title":"Redox Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"LBA5","DOI":"10.1200\/JCO.2026.44.17_suppl.LBA5","article-title":"Daraxonrasib, a RAS(ON) Multi-Selective Inhibitor vs. Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma (MPDAC): Primary and Final Analysis from the Phase 3 RASolute 302 Study","volume":"44","author":"Wolpin","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s40164-025-00647-2","article-title":"Extracellular Matrix Stiffness: Mechanisms in Tumor Progression and Therapeutic Potential in Cancer","volume":"14","author":"Zhang","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13046-024-03262-x","article-title":"Identification and Characterization of Tumor and Stromal Derived Liquid Biopsy Analytes in Pancreatic Ductal Adenocarcinoma","volume":"44","author":"Belloum","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/s41416-025-03019-z","article-title":"Tumor-Stroma Ratio Combined with PD-L1 Identifies Pancreatic Ductal Adenocarcinoma Patients at Risk for Lymph Node Metastases","volume":"132","author":"Chen","year":"2025","journal-title":"Br. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1186\/s12967-025-07119-5","article-title":"ITGB5-Mediated Biomechanical Regulation in Pancreatic Ductal Adenocarcinoma Stroma Impacts Tumor Progression and Prognosis","volume":"23","author":"Yang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eabc4552","DOI":"10.1126\/science.abc4552","article-title":"The Microbiome and Human Cancer","volume":"371","author":"Zitvogel","year":"2021","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1038\/s43018-023-00614-y","article-title":"A First-in-Class Pan-Lysyl Oxidase Inhibitor Impairs Stromal Remodeling and Enhances Gemcitabine Response and Survival in Pancreatic Cancer","volume":"4","author":"Chitty","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.3332\/ecancer.2025.1996","article-title":"Targeting Stromal Components in Pancreatic Ductal Adenocarcinoma: A Review","volume":"19","author":"Shihadeh","year":"2025","journal-title":"Ecancermedicalscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/s41586-024-08225-y","article-title":"Clinical Functional Proteomics of Intercellular Signalling in Pancreatic Cancer","volume":"637","author":"Huang","year":"2024","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3968","DOI":"10.1200\/JCO.2015.63.3651","article-title":"Biomarker: Predictive or Prognostic?","volume":"33","author":"Ballman","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1038\/s41588-024-01914-4","article-title":"Spatial Transcriptomic Analysis of Primary and Metastatic Pancreatic Cancers Highlights Tumor Microenvironmental Heterogeneity","volume":"56","author":"Khaliq","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1038\/s41588-024-01890-9","article-title":"Spatially Resolved Analysis of Pancreatic Cancer Identifies Therapy-Associated Remodeling of the Tumor Microenvironment","volume":"56","author":"Shiau","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41467-024-55330-7","article-title":"Spatial Tumor Immune Heterogeneity Facilitates Subtype Co-Existence and Therapy Response in Pancreatic Cancer","volume":"16","author":"Klein","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17102","DOI":"10.1038\/s41598-025-00517-1","article-title":"Evaluation of Tumor Targets Selected from Public Genomic Databases for Imaging of Pancreatic Ductal Adenocarcinoma","volume":"15","author":"Badr","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"oyae323","DOI":"10.1093\/oncolo\/oyae323","article-title":"Pembrolizumab \u00b1 Paricalcitol in Metastatic Pancreatic Cancer Postmaximal Cytoreduction","volume":"30","author":"Chung","year":"2025","journal-title":"Oncologist"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Aughton, K., Elander, N.O., Evans, A., Jackson, R., Campbell, F., Costello, E., Halloran, C.M., Mackey, J.R., Scarfe, A.G., and Valle, J.W. (2021). HENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA MRNA. Cancers, 13.","DOI":"10.3390\/cancers13225758"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1158\/1078-0432.CCR-22-1630","article-title":"Addition of Losartan to FOLFIRINOX and Chemoradiation Reduces Immunosuppression-Associated Genes, Tregs and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer","volume":"29","author":"Boucher","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1001\/jamaoncol.2019.0892","article-title":"Total Neoadjuvant Therapy with FOLFIRINOX in Combination with Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial","volume":"5","author":"Murphy","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e70985","DOI":"10.1111\/jcmm.70985","article-title":"Current Status of Research on Losartan in Tumour Therapy","volume":"30","author":"Wang","year":"2026","journal-title":"J. Cell. Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/ans.19405","article-title":"Metformin Use and Pancreatic Ductal Adenocarcinoma Outcomes: A Narrative Review","volume":"95","author":"Lee","year":"2025","journal-title":"ANZ J. Surg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4841","DOI":"10.1038\/s41467-020-18636-w","article-title":"Phase I Clinical Trial Repurposing All-Trans Retinoic Acid as a Stromal Targeting Agent for Pancreatic Cancer","volume":"11","author":"Kocher","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1093\/jnci\/djae070","article-title":"Metformin Boosts Antitumor Immunity and Improves Prognosis in Upfront Resected Pancreatic Cancer: An Observational Study","volume":"116","author":"Vadgama","year":"2024","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1001\/jamaoncol.2019.0684","article-title":"Effect of Gemcitabine and Nab-Paclitaxel with or Without Hydroxychloroquine on Patients with Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial","volume":"5","author":"Karasic","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wang, Q., Lv, N., Xu, D., Wu, Y., Wu, J., Gao, W., Wei, J., Xiao, B., Tu, M., and Jiang, K. (2025). Efficacy of Second-Line Treatment for Gemcitabine-Refractory Unresectable Pancreatic Cancer in a Real-World Setting. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-14601-2"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e70343","DOI":"10.1002\/cncr.70343","article-title":"A Randomized Phase II Trial of Gemcitabine, Nab-Paclitaxel, Cisplatin with or without a Medically Supervised Ketogenic Diet for Patients with Metastatic Pancreatic Cancer","volume":"132","author":"Jameson","year":"2026","journal-title":"Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s12967-020-02376-y","article-title":"Antifibrotic Therapy to Normalize the Tumor Microenvironment","volume":"18","author":"Hauge","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s13046-024-03072-1","article-title":"Three-Dimensional Environment Sensitizes Pancreatic Cancer Cells to the Anti-Proliferative Effect of Budesonide by Reprogramming Energy Metabolism","volume":"43","author":"Ibello","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_61","first-page":"e2078","article-title":"Statins as Anti-Tumor Agents: A Paradigm for Repurposed Drugs","volume":"7","author":"Tripathi","year":"2024","journal-title":"Cancer Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/ajg.2015.217","article-title":"Impact of Statin Use on Survival in Patients Undergoing Resection for Early-Stage Pancreatic Cancer","volume":"110","author":"Wu","year":"2015","journal-title":"Am. J. Gastroenterol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.1002\/jcb.27719","article-title":"Itraconazole Inhibits Proliferation of Pancreatic Cancer Cells through Activation of Bak-1","volume":"120","author":"Jiang","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"483","DOI":"10.5009\/gnl250028","article-title":"Disulfiram\/Copper Complex Induces Cytotoxicity in Pancreatic Cancer Cells and 5-Fluorouracil-Resistant Cells through Nuclear Factor E2-Related Factor-2 Suppression and Reactive Oxygen Species Modulation","volume":"20","author":"Kim","year":"2026","journal-title":"Gut Liver"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.semcancer.2025.01.003","article-title":"Leveraging Epigenetic Alterations in Pancreatic Ductal Adenocarcinoma for Clinical Applications","volume":"109","author":"Tost","year":"2025","journal-title":"Semin. Cancer Biol."},{"key":"ref_66","unstructured":"(2026, August 18). Istituti Fisioterapici Ospitalieri Clinical Trials Register. Available online: https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/trial\/2021-002632-23\/IT?utm."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Budillon, A., Leone, A., Passaro, E., Silvestro, L., Foschini, F., Iannelli, F., Roca, M.S., Macchini, M., Bruzzese, F., and Garcia Bermejo, M.L. (2024). Randomized Phase 2 Study of Valproic Acid Combined with Simvastatin and Gemcitabine\/Nab-Paclitaxel-Based Regimens in Untreated Metastatic Pancreatic Adenocarcinoma Patients: The VESPA Trial Study Protocol. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12936-w"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"eadp0684","DOI":"10.1126\/sciadv.adp0684","article-title":"Semaphorin 3D Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming","volume":"10","author":"Thielman","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"12639","DOI":"10.1021\/acs.jmedchem.2c00201","article-title":"Designing Soluble PROTACs: Strategies and Preliminary Guidelines","volume":"65","author":"Vallaro","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"12177","DOI":"10.2147\/IJN.S552644","article-title":"Nanotechnology Advances Proteolysis Targeting Chimeras (PROTACs): Transition from Basic Research to Clinical Application","volume":"20","author":"Mu","year":"2025","journal-title":"Int. J. Nanomed."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"118892","DOI":"10.1016\/j.biopha.2025.118892","article-title":"PROTAC Delivery Systems: Innovative Approaches for Cancer Treatment","volume":"194","author":"Bravo","year":"2026","journal-title":"Biomed. Pharmacother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1080\/02656736.2017.1336675","article-title":"Hyperthermia-Enhanced Targeted Drug Delivery Using Magnetic Resonance-Guided Focussed Ultrasound: A Pre-Clinical Study in a Genetic Model of Pancreatic Cancer","volume":"34","author":"Farr","year":"2018","journal-title":"Int. J. Hyperth."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"100222","DOI":"10.1016\/j.celbio.2025.100222","article-title":"Nanotechnology for Tumor Ferroptosis","volume":"2","author":"Wang","year":"2025","journal-title":"Cell Biomater."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5440","DOI":"10.1158\/1078-0432.CCR-22-1788","article-title":"Fibroblast Activation Protein Triggers Release of Drug Payload from Non-Internalizing Small Molecule Drug Conjugates in Solid Tumors","volume":"28","author":"Zana","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.jcis.2023.12.166","article-title":"Enhancing Pancreatic Ductal Adenocarcinoma (PDAC) Therapy with Targeted Carbon Nano-Onion (CNO)-Mediated Delivery of Gemcitabine (GEM)-Derived Prodrugs","volume":"659","author":"Bartkowski","year":"2024","journal-title":"J. Colloid Interface Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"114673","DOI":"10.1016\/j.jconrel.2026.114673","article-title":"New-Generation Advanced Nano-PROTACs as Potential Therapeutic Agents in Cancer Therapy","volume":"392","author":"Zhang","year":"2026","journal-title":"J. Control. Release"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"28502","DOI":"10.1021\/acsnano.4c09800","article-title":"Advancing Proteolysis Targeting Chimera (PROTAC) Nanotechnology in Protein Homeostasis Reprograming for Disease Treatment","volume":"18","author":"Wu","year":"2024","journal-title":"ACS Nano"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1053\/j.gastro.2018.03.029","article-title":"Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial","volume":"155","author":"Beatty","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41591-025-04043-5","article-title":"Autologous Multiantigen-Targeted T Cell Therapy for Pancreatic Cancer: A Phase 1\/2 Trial","volume":"32","author":"Musher","year":"2026","journal-title":"Nat. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"102301","DOI":"10.1016\/j.xcrm.2025.102301","article-title":"Clinical and Molecular Dissection of CAR T Cell Resistance in Pancreatic Cancer","volume":"6","author":"Aznar","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1158\/1078-0432.CCR-23-3841","article-title":"Mesothelin CAR T-Cells Secreting Anti-FAP\/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and Its Stroma","volume":"30","author":"Wehrli","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1158\/2767-9764.CRC-24-0226","article-title":"Therapeutic Efficacy of IL7\/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer","volume":"4","author":"Ohta","year":"2024","journal-title":"Cancer Res. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"106329","DOI":"10.1016\/j.phrs.2022.106329","article-title":"Locoregional Delivery of CAR-T Cells in the Clinic","volume":"182","author":"Sagnella","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1136\/gutjnl-2018-316595","article-title":"Switchable CAR-T Cells Mediate Remission in Metastatic Pancreatic Ductal Adenocarcinoma","volume":"68","author":"Raj","year":"2018","journal-title":"Gut"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4001","DOI":"10.1016\/j.ymthe.2026.03.012","article-title":"T Cell Receptor Gene Therapy Targeting KRAS G12V for Advanced Pancreatic Cancer in a Single-Arm Phase 1\/2 Clinical Trial","volume":"34","author":"Xu","year":"2026","journal-title":"Mol. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1056\/NEJMoa2119662","article-title":"Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer","volume":"386","author":"Leidner","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13046-023-02935-3","article-title":"Tumor Immune Microenvironment-Based Therapies in Pancreatic Ductal Adenocarcinoma: Time to Update the Concept","volume":"43","author":"Luo","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"116827","DOI":"10.1016\/j.celrep.2025.116827","article-title":"In Situ Multi-Modal Characterization of Pancreatic Cancer Reveals Tumor Cell Identity as a Defining Factor of the Surrounding Microenvironment","volume":"45","author":"Lyubetskaya","year":"2026","journal-title":"Cell Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.1039\/D3NR06059D","article-title":"Nano-PROTACs: State of the Art and Perspectives","volume":"16","author":"Zhong","year":"2024","journal-title":"Nanoscale"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1200\/JCO.2020.38.4_suppl.638","article-title":"Randomized Phase III Trial of Pegvorhyaluronidase Alfa with Nab-Paclitaxel Plus Gemcitabine for Patients with Hyaluronan-High Metastatic Pancreatic Adenocarcinoma","volume":"38","author":"Tempero","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.jhep.2020.11.037","article-title":"CD40-Mediated Immune Cell Activation Enhances Response to Anti-PD-1 in Murine Intrahepatic Cholangiocarcinoma","volume":"74","author":"Diggs","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1038\/s41591-022-01829-9","article-title":"Sotigalimab and\/or Nivolumab with Chemotherapy in First-Line Metastatic Pancreatic Cancer: Clinical and Immunologic Analyses from the Randomized Phase 2 PRINCE Trial","volume":"28","author":"Maurer","year":"2022","journal-title":"Nat. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S1470-2045(24)00263-8","article-title":"Combining CD40 Agonist Mitazalimab with MFOLFIRINOX in Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma (OPTIMIZE-1): A Single-Arm, Multicentre Phase 1b\/2 Study","volume":"25","author":"Borbath","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"S147","DOI":"10.1016\/j.annonc.2025.05.399","article-title":"384TiP Quemliclustat and Chemotherapy in Previously Untreated Patients with Metastatic Pancreatic Ductal Adenocarcinoma: PRISM-1, a Randomized, Placebo-Controlled, Phase III Trial","volume":"36","author":"Mercade","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.cpet.2023.02.007","article-title":"Fibroblast Activation Protein Inhibitor Theranostics: Early Clinical Translation","volume":"18","author":"Mori","year":"2023","journal-title":"PET Clin."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1158\/2159-8290.CD-19-0094","article-title":"Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts","volume":"9","author":"Elyada","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Perez, V.M., Kearney, J.F., and Yeh, J.J. (2021). The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.751311"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.12659\/MSM.892523","article-title":"Disrupting the Balance between Tumor Epithelia and Stroma Is a Possible Therapeutic Approach for Pancreatic Cancer","volume":"20","author":"Wang","year":"2014","journal-title":"Med. Sci. Monit."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Anderson, E.M., Thomassian, S., Gong, J., Hendifar, A., and Osipov, A. (2021). Advances in Pancreatic Ductal Adenocarcinoma Treatment. Cancers, 13.","DOI":"10.3390\/cancers13215510"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Myo Min, K.K., Ffrench, C.B., Jessup, C.F., Shepherdson, M., Barreto, S.G., and Bonder, C.S. (2023). Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities. Cancers, 15.","DOI":"10.3390\/cancers15082354"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Shakfa, N., Nowlan, F., Drissler, S., Tan, T.J., Sunnucks, E., Chen, E.L.Y., Wong, C.J., Seale, B., Lin, Z.-Y., and Chan-Seng-Yue, M. (2025). Integrated Spatial Proteomics of Human PDAC Uncovers an Expanded Tumour\u2013Immune\u2013 Stroma Spectrum with Genomic Associations. bioRxiv.","DOI":"10.1101\/2025.08.15.670565"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s43046-025-00334-7","article-title":"Cancer-Associated Fibroblasts at the Crossroads of Tumor Progression and Therapy Resistance: From Heterogeneity to Precision Reprogramming","volume":"37","author":"Adusumalli","year":"2025","journal-title":"J. Egypt. Natl. Cancer Inst."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6075403","DOI":"10.1155\/2018\/6075403","article-title":"Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts","volume":"2018","author":"Avagliano","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Cozzo, A.J., Coleman, M.F., Pearce, J.B., Pfeil, A.J., Etigunta, S.K., and Hursting, S.D. (2020). Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.590192"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Li, W.N., Zhang, S.J., Feng, J.Q., and Jin, W.L. (2022). Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment. Cancers, 14.","DOI":"10.3390\/cancers14112608"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Zhang, D., Lindstrom, A., Kim, E.J., Hwang, C.-I., Hall, M.L., Lin, T.Y., and Li, Y. (2022). SEMA3C Supports Pancreatic Cancer Progression by Regulating the Autophagy Process and Tumor Immune Microenvironment. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.890154"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s12951-025-03985-9","article-title":"Nano-PROTACs for Precision Medicine: Engineering Strategies for Enhanced Targeting and Potency","volume":"24","author":"Yang","year":"2026","journal-title":"J. Nanobiotechnol."},{"key":"ref_108","first-page":"E2","article-title":"PROTACS-A New Generation of Poorly Soluble and Permeable Molecules for Targeting Proteins","volume":"3","author":"Ali","year":"2026","journal-title":"J. Nanomed."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Khabipov, A., Trung, D.N., van der Linde, J., Miebach, L., Lenz, M., Erne, F., von Bernstorff, W., Schulze, T., Kersting, S., and Bekeschus, S. (2023). CCR4 Blockade Diminishes Intratumoral Macrophage Recruitment and Augments Survival of Syngeneic Pancreatic Cancer-Bearing Mice. Biomedicines, 11.","DOI":"10.3390\/biomedicines11061517"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/s41590-025-02134-6","article-title":"Macrophages and Fibroblasts as Regulators of the Immune Response in Pancreatic Cancer","volume":"26","author":"Shakiba","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4429","DOI":"10.1158\/1078-0432.CCR-17-0162","article-title":"Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers","volume":"23","author":"Knudsen","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_112","first-page":"1405","article-title":"Integrated Pretreatment Stratification System for Pancreatic Cancer: Combining Anatomical Resectability and Tumor Biological Parameters","volume":"22","author":"Gao","year":"2025","journal-title":"Cancer Biol. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1637\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:16:07Z","timestamp":1789186567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":112,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15181637"],"URL":"https:\/\/doi.org\/10.3390\/cells15181637","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}