{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T02:58:29Z","timestamp":1793674709460,"version":"4.5.1"},"reference-count":199,"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":[{"name":"Fiona Elsey Cancer Research Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer with low five-year overall survival rates of ~10% from diagnosis. The immune \u2018cold\u2019 tumor microenvironment (TME) of PDAC is a key contributor to tumor progression, featuring immunosuppression in conjunction with a reactive stroma. The immune composition of the TME is highly tumor-promoting, with the presence of immunosuppressive cells and the absence of effector and cytotoxic immune cells. Further to this, the active stroma region of the tumors contains transformed fibroblasts which communicate with tumor and immune cells to further enhance immunosuppression. Fundamental cellular processes such as T cell exhaustion, metabolic signaling, epigenetic modifications, and a series of genetic mutations can all contribute to PDAC progression and poor patient outcomes. This review describes the key mechanisms behind immune dysregulation in PDAC, highlighting the importance of this area and the essential research that is necessary.<\/jats:p>","DOI":"10.3390\/biology15181599","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:54:19Z","timestamp":1789055659000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanisms of Immune Cell Dysregulation in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Farah","family":"Ahmady-Nield","sequence":"first","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University Australia, Mt Helen, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney B.","family":"Luwor","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University Australia, Mt Helen, Ballarat, VIC 3350, Australia"},{"name":"Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6880-9795","authenticated-orcid":false,"given":"George","family":"Kannourakis","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University Australia, Mt Helen, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17562848251414188","DOI":"10.1177\/17562848251414188","article-title":"Differentiating cytology of pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors by EUS-FNA through hyperspectral imaging technology combined with artificial intelligence","volume":"19","author":"Qin","year":"2026","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"833","DOI":"10.4251\/wjgo.v12.i8.833","article-title":"One size does not fit all for pancreatic cancers: A review on rare histologies and therapeutic approaches","volume":"12","author":"Niger","year":"2020","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1097\/MPA.0000000000001338","article-title":"Characteristics and Outcomes of Pancreatic Cancer by Histological Subtypes","volume":"48","author":"Luo","year":"2019","journal-title":"Pancreas"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113941","DOI":"10.1016\/j.ejca.2024.113941","article-title":"Corrigendum to \u201cRisk factors for early-onset pancreatic ductal adenocarcinoma: A systematic literature review\u201d","volume":"201","author":"Chandana","year":"2024","journal-title":"Eur. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cysneiros, M., Cirqueira, M.B., Barbosa, L.F., Chaves de Oliveira, E., Morais, L.K., Wastowski, I.J., and Floriano, V.G. (2024). Immune cells and checkpoints in pancreatic adenocarcinoma: Association with clinical and pathological characteristics. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0305648"},{"key":"ref_7","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Peshin, S., Takrori, E., Kodali, N.A., Bashir, F., and Singal, S. (2025). Advances in the Management of Pancreatic Cancer: Current Strategies and Emerging Therapies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157055"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ejso.2016.10.023","article-title":"Radical surgery of oligometastatic pancreatic cancer","volume":"43","author":"Hackert","year":"2017","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: From T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zheng, R., Liu, X., Zhang, Y., Liu, Y., Wang, Y., Guo, S., Jin, X., Zhang, J., Guan, Y., and Liu, Y. (2024). Frontiers and future of immunotherapy for pancreatic cancer: From molecular mechanisms to clinical application. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1383978"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hayat, U., Croce, P.S., Saadeh, A., Desai, K., Appiah, J., Khan, S., Khan, Y.I., Kumar, K., and Hanif, A. (2025). Current and Emerging Treatment Options for Pancreatic Cancer: A Comprehensive Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14041129"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Di Federico, A., Mosca, M., Pagani, R., Carloni, R., Frega, G., De Giglio, A., Rizzo, A., Ricci, D., Tavolari, S., and Di Marco, M. (2022). Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes. Cancers, 14.","DOI":"10.3390\/cancers14102429"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1007\/s00262-017-2053-4","article-title":"CTLA-4\/CD80 pathway regulates T cell infiltration into pancreatic cancer","volume":"66","author":"Bengsch","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1093\/annonc\/mdu205","article-title":"A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer","volume":"25","author":"Aglietta","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3871","DOI":"10.3390\/curroncol30040293","article-title":"Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights","volume":"30","author":"Balsano","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"191939","DOI":"10.1172\/JCI191939","article-title":"KRAS: The Achilles\u2019 heel of pancreas cancer biology","volume":"135","author":"Talabi","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Linehan, A., O\u2019Reilly, M., McDermott, R., and O\u2019Kane, G.M. (2024). Targeting KRAS mutations in pancreatic cancer: Opportunities for future strategies. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1369136"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1056\/NEJMoa2605555","article-title":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","volume":"395","author":"Wainberg","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"78","DOI":"10.18632\/genesandcancer.171","article-title":"Desmoplasia in pancreatic ductal adenocarcinoma: Insight into pathological function and therapeutic potential","volume":"9","author":"Cannon","year":"2018","journal-title":"Genes. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Saka, D., Gokalp, M., Piyade, B., Cevik, N.C., Arik Sever, E., Unutmaz, D., Ceyhan, G.O., Demir, I.E., and Asimgil, H. (2020). Mechanisms of T-Cell Exhaustion in Pancreatic Cancer. Cancers, 12.","DOI":"10.3390\/cancers12082274"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Javadrashid, D., Baghbanzadeh, A., Derakhshani, A., Leone, P., Silvestris, N., Racanelli, V., Solimando, A.G., and Baradaran, B. (2021). Pancreatic Cancer Signaling Pathways, Genetic Alterations, and Tumor Microenvironment: The Barriers Affecting the Method of Treatment. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040373"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/bs.pmbts.2016.09.008","article-title":"Molecular Pathogenesis of Pancreatic Cancer","volume":"144","author":"Grant","year":"2016","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Joseph, A.M., Al Aiyan, A., Al-Ramadi, B., Singh, S.K., and Kishore, U. (2024). Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1323198"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/s41422-019-0212-1","article-title":"Author Correction: Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma","volume":"29","author":"Peng","year":"2019","journal-title":"Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41416-019-0479-5","article-title":"Tumour microenvironment of pancreatic cancer: Immune landscape is dictated by molecular and histopathological features","volume":"121","author":"Karamitopoulou","year":"2019","journal-title":"Br. J. Cancer."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1002\/jso.27581","article-title":"Characterization of natural killer and cytotoxic T-cell immune infiltrates in pancreatic ductal adenocarcinoma","volume":"129","author":"Persky","year":"2024","journal-title":"J. Surg. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41571-020-0363-5","article-title":"The tumour microenvironment in pancreatic cancer\u2014Clinical challenges and opportunities","volume":"17","author":"Ho","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41698-024-00681-z","article-title":"Barriers and opportunities in pancreatic cancer immunotherapy","volume":"8","author":"Ju","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1053\/j.gastro.2023.05.036","article-title":"Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer","volume":"165","author":"Yousuf","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s44272-023-00005-5","article-title":"The role of innate immune cells as modulators of the tumor microenvironment in the metastasis and treatment of pancreatic cancer","volume":"2","author":"Zhu","year":"2023","journal-title":"Clin. Cancer Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.cytogfr.2025.11.003","article-title":"Targeting cytokines: Reshaping the pancreatic tumor microenvironment","volume":"86","author":"Bandi","year":"2025","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"D\u2019Angelo, A., Sobhani, N., Roviello, G., Bagby, S., Bonazza, D., Bottin, C., Giudici, F., Zanconati, F., De Manzini, N., and Guglielmi, A. (2019). Tumour infiltrating lymphocytes and immune-related genes as predictors of outcome in pancreatic adenocarcinoma. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0219566"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bernard, B., Rajamanickam, V., Dubay, C., Piening, B., Alonso, E., Jutric, Z., Tang, E., Newell, P., Hansen, P., and Medler, T. (2020). Transcriptional and immunohistological assessment of immune infiltration in pancreatic cancer. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238380"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kiryu, S., Ito, Z., Suka, M., Bito, T., Kan, S., Uchiyama, K., Saruta, M., Hata, T., Takano, Y., and Fujioka, S. (2021). Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08911-4"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"217699","DOI":"10.1016\/j.canlet.2025.217699","article-title":"Tumor immune microenvironment in pancreatic ductal adenocarcinoma revisited\u2014Exploring the \u201cSpace\u201d","volume":"622","author":"Brautigam","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1158\/1078-0432.CCR-24-0368","article-title":"Spatial Heterogeneity of Immune Regulators Drives Dynamic Changes in Local Immune Responses, Affecting Disease Outcomes in Pancreatic Cancer","volume":"30","author":"Karamitopoulou","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.ejca.2012.10.022","article-title":"Tumour budding is a strong and independent prognostic factor in pancreatic cancer","volume":"49","author":"Karamitopoulou","year":"2013","journal-title":"Eur. J. Cancer."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"218613","DOI":"10.1016\/j.canlet.2026.218613","article-title":"Single-cell spatial transcriptional profiling of pancreatic ductal adenocarcinoma uncovers key immune-modulating and pro-metastatic mechanisms","volume":"655","author":"Zhou","year":"2026","journal-title":"Cancer Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1038\/s41467-024-55424-2","article-title":"Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms","volume":"16","author":"Sivakumar","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1053\/j.gastro.2013.07.025","article-title":"Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma","volume":"145","author":"Clear","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s43018-020-00121-4","article-title":"Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer","volume":"1","author":"Steele","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mazur, A., Holthoff, E., Vadali, S., Kelly, T., and Post, S.R. (2016). Cleavage of Type I Collagen by Fibroblast Activation Protein-alpha Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150287"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nm.2344","article-title":"Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy","volume":"17","author":"Collisson","year":"2011","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic analyses identify molecular subtypes of pancreatic cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ccell.2017.07.007","article-title":"Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma","volume":"32","author":"Raphael","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/ng.3398","article-title":"Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma","volume":"47","author":"Moffitt","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.canlet.2019.10.031","article-title":"Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma","volume":"469","author":"Hiroshima","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.2147\/OTT.S201675","article-title":"ITGA3 serves as a diagnostic and prognostic biomarker for pancreatic cancer","volume":"12","author":"Jiao","year":"2019","journal-title":"Onco Targets Ther."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Liot, S., Balas, J., Aubert, A., Prigent, L., Mercier-Gouy, P., Verrier, B., Bertolino, P., Hennino, A., Valcourt, U., and Lambert, E. (2021). Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.612271"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Manoukian, P., Bijlsma, M., and van Laarhoven, H. (2021). The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.743907"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.3390\/cancers7040902","article-title":"Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth","volume":"7","author":"Shiga","year":"2015","journal-title":"Cancers"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13045-025-01688-0","article-title":"Cancer associated fibroblasts in cancer development and therapy","volume":"18","author":"Jia","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1053\/j.gastro.2018.12.044","article-title":"Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets","volume":"156","author":"Whittle","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Huber, M., Brehm, C.U., Gress, T.M., Buchholz, M., Alashkar Alhamwe, B., von Strandmann, E.P., Slater, E.P., Bartsch, J.W., Bauer, C., and Lauth, M. (2020). The Immune Microenvironment in Pancreatic Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197307"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"216859","DOI":"10.1016\/j.canlet.2024.216859","article-title":"Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: Challenges and opportunities","volume":"591","author":"Qin","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e70415","DOI":"10.1002\/mco2.70415","article-title":"Cancer-Associated Fibroblasts: Origin, Classification, Tumorigenicity, and Targeting for Cancer Therapy","volume":"6","author":"Fan","year":"2025","journal-title":"MedComm"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20162024","article-title":"Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer","volume":"214","author":"Ohlund","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1002\/stem.3455","article-title":"ELF3 mediates IL-1alpha induced differentiation of mesenchymal stem cells to inflammatory iCAFs","volume":"39","author":"Tran","year":"2021","journal-title":"Stem Cells"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1158\/2159-8290.CD-18-0710","article-title":"IL1-Induced JAK\/STAT Signaling Is Antagonized by TGFbeta to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Biffi","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_61","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_62","doi-asserted-by":"crossref","unstructured":"Monteran, L., and Erez, N. (2019). The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01835"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1186\/s12967-025-07164-0","article-title":"Metabolic and immune crosstalk between cancer-associated fibroblasts and pancreatic cancer cells","volume":"23","author":"Zhang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0016-5085(03)01064-3","article-title":"Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer","volume":"125","author":"Scholz","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5395","DOI":"10.1158\/0008-5472.CAN-15-3264","article-title":"Cancer-Associated Fibroblasts in Pancreatic Cancer Are Reprogrammed by Tumor-Induced Alterations in Genomic DNA Methylation","volume":"76","author":"Xiao","year":"2016","journal-title":"Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1097\/MPA.0000000000001249","article-title":"Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function","volume":"48","author":"Begum","year":"2019","journal-title":"Pancreas"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3892\/ijo.2016.3779","article-title":"Prometastatic mechanisms of CAF-mediated EMT regulation in pancreatic cancer cells","volume":"50","author":"Shan","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1111\/cas.16418","article-title":"Cancer-associated fibroblast-derived MMP11 promotes tumor progression in pancreatic cancer","volume":"116","author":"Wang","year":"2025","journal-title":"Cancer Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1053\/j.gastro.2012.11.037","article-title":"A starring role for stellate cells in the pancreatic cancer microenvironment","volume":"144","author":"Apte","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_70","first-page":"550","article-title":"Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma","volume":"61","author":"Lohr","year":"2001","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1158\/1078-0432.CCR-08-0291","article-title":"Sonic hedgehog promotes desmoplasia in pancreatic cancer","volume":"14","author":"Bailey","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1053\/j.gastro.2004.12.036","article-title":"Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells","volume":"128","author":"Bachem","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Stouten, I., van Montfoort, N., and Hawinkels, L. (2023). The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108707"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"218331","DOI":"10.1016\/j.canlet.2026.218331","article-title":"Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p\/STING\/LGALS1 pathway","volume":"644","author":"Zhang","year":"2026","journal-title":"Cancer Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"17071","DOI":"10.1038\/s41598-024-68061-y","article-title":"Activation of STING in pancreatic cancer-associated fibroblasts exerts an antitumor effect by enhancing tumor immunity","volume":"14","author":"Suzuki","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ccell.2015.11.002","article-title":"Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival","volume":"28","author":"Ozdemir","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.cca.2011.11.006","article-title":"Surface markers of lymphocyte activation and markers of cell proliferation","volume":"413","author":"Shipkova","year":"2012","journal-title":"Clin. Chim. Acta"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/imcb.12636","article-title":"T-cell activation-induced marker assays in health and disease","volume":"101","author":"Poloni","year":"2023","journal-title":"Immunol. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jim.2004.07.006","article-title":"Comparative analysis of lymphocyte activation marker expression and cytokine secretion profile in stimulated human peripheral blood mononuclear cell cultures: An in vitro model to monitor cellular immune function","volume":"293","author":"Reddy","year":"2004","journal-title":"J. Immunol. Methods"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"8045161","DOI":"10.1155\/2017\/8045161","article-title":"The Distribution of Activation Markers and Selectins on Peripheral T Lymphocytes in Preeclampsia","volume":"2017","author":"Bajnok","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"113443","DOI":"10.1016\/j.jim.2023.113443","article-title":"An optimized flow cytometry protocol for simultaneous detection of T cell activation induced markers and intracellular cytokines: Application to SARS-CoV-2 immune individuals","volume":"515","author":"Altosole","year":"2023","journal-title":"J. Immunol. Methods"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/s41422-020-0277-x","article-title":"The yin and yang of co-inhibitory receptors: To-ward anti-tumor immunity without autoimmunity","volume":"30","author":"Schnell","year":"2020","journal-title":"Cell Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/ni0702-611","article-title":"CTLA-4: New insights into its biological function and use in tumor immunotherapy","volume":"3","author":"Egen","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.immuni.2018.04.026","article-title":"Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells","volume":"48","author":"Bengsch","year":"2018","journal-title":"Immunity"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.immuni.2016.07.011","article-title":"Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis","volume":"45","author":"Schietinger","year":"2016","journal-title":"Immunity"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/nri2818","article-title":"NFAT, immunity and cancer: A transcription factor comes of age","volume":"10","author":"Muller","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1038\/sj.emboj.7601246","article-title":"Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+\/calcineurin signaling pathway","volume":"25","author":"Buchholz","year":"2006","journal-title":"EMBO J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"15419","DOI":"10.1073\/pnas.1206370109","article-title":"Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1","volume":"109","author":"Xiao","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.immuni.2017.11.021","article-title":"Transcription Factor IRF4 Promotes CD8(+) T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection","volume":"47","author":"Man","year":"2017","journal-title":"Immunity"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","article-title":"TOX is a critical regulator of tumour-specific T cell differentiation","volume":"571","author":"Scott","year":"2019","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"12410","DOI":"10.1073\/pnas.1905675116","article-title":"TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion","volume":"116","author":"Seo","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1146\/annurev-immunol-032712-095956","article-title":"Metabolic regulation of T lymphocytes","volume":"31","author":"MacIver","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.cell.2013.05.016","article-title":"Posttranscriptional control of T cell effector function by aerobic glycolysis","volume":"153","author":"Chang","year":"2013","journal-title":"Cell"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Saleem, M.U., Sajid, H.A., Arshad, M.W., Torres, A.O.R., Shabbir, M.I., and Rai, S.K. (2025). Novel Insights into T-Cell Exhaustion and Cancer Biomarkers in PDAC Using ScRNA-Seq. Biology, 14.","DOI":"10.1101\/2025.01.13.632574"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/CJI.0000000000000111","article-title":"Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer","volume":"39","author":"Meng","year":"2016","journal-title":"J. Immunother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1002\/ijc.26290","article-title":"High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer","volume":"130","author":"Tang","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"7956","DOI":"10.3748\/wjg.v27.i46.7956","article-title":"T cells in pancreatic cancer stroma","volume":"27","author":"Goulart","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Sivakumar, S., Abu-Shah, E., Ahern, D.J., Arbe-Barnes, E.H., Jainarayanan, A.K., Mangal, N., Reddy, S., Rendek, A., Easton, A., and Kurz, E. (2021). Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer. Cancers, 13.","DOI":"10.3390\/cancers13081776"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1038\/s41467-023-39680-2","article-title":"Author Correction: Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment","volume":"14","author":"Werba","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Yang, X., Wang, G., Song, Y., Zhuang, T., Li, Y., Xie, Y., Fei, X., Zhao, Y., Xu, D., and Hu, Y. (2023). PD-1(+)CD8(+) T Cells Proximal to PD-L1(+)CD68(+) Macrophages Are Associated with Poor Prognosis in Pancreatic Ductal Adenocarcinoma Patients. Cancers, 15.","DOI":"10.3390\/cancers15051389"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.1158\/0008-5472.CAN-13-3723","article-title":"CSF1\/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models","volume":"74","author":"Zhu","year":"2014","journal-title":"Cancer Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.ccr.2012.04.025","article-title":"Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer","volume":"21","author":"Bayne","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/CJI.0b013e31829fb7a2","article-title":"Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer","volume":"36","author":"Le","year":"2013","journal-title":"J. Immunother."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CJI.0000000000000062","article-title":"PD-1\/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors","volume":"38","author":"Soares","year":"2015","journal-title":"J. Immunother."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3435","DOI":"10.1172\/JCI128562","article-title":"In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors","volume":"129","author":"Khalil","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature13490","article-title":"Functional polarization of tumour-associated macrophages by tumour-derived lactic acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"8602","DOI":"10.1126\/sciadv.abi8602","article-title":"Lactate supports a metabolic-epigenetic link in macrophage polarization","volume":"7","author":"Noe","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.tcb.2025.04.007","article-title":"Tumor-stromal metabolic crosstalk in pancreatic cancer","volume":"35","author":"Thakur","year":"2025","journal-title":"Trends Cell Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1158\/2326-6066.CIR-20-0111","article-title":"Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer","volume":"8","author":"Yang","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1038\/s41467-018-04366-7","article-title":"Single cell analysis of kynurenine and System L amino acid transport in T cells","volume":"9","author":"Sinclair","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/ni.2556","article-title":"Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation","volume":"14","author":"Sinclair","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2016.09.031","article-title":"L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity","volume":"167","author":"Geiger","year":"2016","journal-title":"Cell"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.immuni.2014.04.007","article-title":"Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation","volume":"40","author":"Nakaya","year":"2014","journal-title":"Immunity"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41556-020-00615-4","article-title":"Asparagine enhances LCK signalling to potentiate CD8(+) T-cell activation and anti-tumour responses","volume":"23","author":"Wu","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12937-020-00628-7","article-title":"Vitamin B6, vitamin B12 and methionine and risk of pancreatic cancer: A meta-analysis","volume":"19","author":"Wei","year":"2020","journal-title":"Nutr. J."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1158\/2159-8290.CD-23-0334","article-title":"Vitamin B6 Competition in the Tumor Microenvironment Hampers Antitumor Functions of NK Cells","volume":"14","author":"He","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"110792","DOI":"10.1016\/j.celrep.2022.110792","article-title":"The lactate-NAD(+) axis activates cancer-associated fibroblasts by downregulating p62","volume":"39","author":"Linares","year":"2022","journal-title":"Cell Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/s41556-024-01417-8","article-title":"Author Correction: Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis","volume":"26","author":"Murthy","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"101079","DOI":"10.1016\/j.gendis.2023.101079","article-title":"CYP3A5 unexpectedly regulates glucose metabolism through the AKT-TXNIP-GLUT1 axis in pancreatic cancer","volume":"11","author":"Shao","year":"2024","journal-title":"Genes Dis."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3669","DOI":"10.1002\/bit.27869","article-title":"Nonviral siRNA delivery systems for pancreatic cancer therapy","volume":"118","author":"Aghamiri","year":"2021","journal-title":"Biotechnol. Bioeng."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"189373","DOI":"10.1016\/j.bbcan.2025.189373","article-title":"Lactate metabolism reprogramming in PDAC: Potential for tumor therapy","volume":"1880","author":"Gao","year":"2025","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Elrakaybi, A., Ruess, D.A., Lubbert, M., Quante, M., and Becker, H. (2022). Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment. Cancers, 14.","DOI":"10.3390\/cancers14235926"},{"key":"ref_128","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_129","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.molonc.2009.03.004","article-title":"Characterizing DNA methylation patterns in pancreatic cancer genome","volume":"3","author":"Tan","year":"2009","journal-title":"Mol. Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1158\/1055-9965.EPI-21-0400","article-title":"Integrating Genome and Methylome Data to Identify Candidate DNA Methylation Biomarkers for Pancreatic Cancer Risk","volume":"30","author":"Zhu","year":"2021","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1053\/j.gastro.2021.04.044","article-title":"TET2 Drives 5hmc Marking of GATA6 and Epigenetically Defines Pancreatic Ductal Adenocarcinoma Transcriptional Subtypes","volume":"161","author":"Eyres","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41392-021-00769-z","article-title":"Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism","volume":"6","author":"Zhang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Wright, C.A., Gordon, E.R., and Cooper, S.J. (2023). Genomic analysis reveals HDAC1 regulates clinically relevant transcriptional programs in Pancreatic cancer. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-11645-0"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1111\/cas.13700","article-title":"Role of histone deacetylase 1 in distant metastasis of pancreatic ductal cancer","volume":"109","author":"Shinke","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1158\/0008-5472.CAN-20-3209","article-title":"HDAC2 Facilitates Pancreatic Cancer Metastasis","volume":"82","author":"Krauss","year":"2022","journal-title":"Cancer Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"6004","DOI":"10.3748\/wjg.v27.i36.6004","article-title":"Histone methylation in pancreatic cancer and its clinical implications","volume":"27","author":"Liu","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41392-020-00252-1","article-title":"The role of histone methylation in the development of digestive cancers: A potential direction for cancer management","volume":"5","author":"Chen","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1158\/0008-5472.CAN-22-2945","article-title":"A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer","volume":"84","author":"Brown","year":"2024","journal-title":"Cancer Res."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s41065-023-00280-1","article-title":"EZH2 regulates pancreatic cancer cells through E2F1, GLI1, CDK3, and Mcm4","volume":"160","author":"Li","year":"2023","journal-title":"Hereditas"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/S0968-0004(00)01689-3","article-title":"What does \u2018chromatin remodeling\u2019 mean?","volume":"25","author":"Aalfs","year":"2000","journal-title":"Trends Biochem. Sci."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nrm.2017.26","article-title":"Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes","volume":"18","author":"Clapier","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Szczepanski, J.M., Rudolf, M.A., and Shi, J. (2024). Clinical Evaluation of the Pancreatic Cancer Microenvironment: Opportunities and Challenges. Cancers, 16.","DOI":"10.3390\/cancers16040794"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"E252","DOI":"10.1073\/pnas.1114817109","article-title":"Convergent structural alterations define SWItch\/Sucrose NonFermentable (SWI\/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer","volume":"109","author":"Shain","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"6744","DOI":"10.1038\/ncomms7744","article-title":"Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets","volume":"6","author":"Witkiewicz","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Han, W., Shi, D., Yang, Q., Li, X., Zhang, J., Peng, C., and Yan, F. (2024). Alteration of chromosome structure impacts gene expressions implicated in pancreatic ductal adenocarcinoma cells. BMC Genom., 25.","DOI":"10.1186\/s12864-024-10109-4"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Hasan, N., and Ahuja, N. (2019). The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer. Cancers, 11.","DOI":"10.3390\/cancers11121859"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/cas.14768","article-title":"The role of the SWI\/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma","volume":"112","author":"Tsuda","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Wieczorek, M., Abualrous, E.T., Sticht, J., Alvaro-Benito, M., Stolzenberg, S., Noe, F., and Freund, C. (2017). Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00292"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1038\/s41467-018-04383-6","article-title":"Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes","volume":"9","author":"Lomberk","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nrg.2016.13","article-title":"Epigenetic modulators, modifiers and mediators in cancer aetiology and progression","volume":"17","author":"Feinberg","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2015.10.020","article-title":"Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses","volume":"164","author":"Chiappinelli","year":"2016","journal-title":"Cell"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.cell.2015.07.056","article-title":"DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts","volume":"162","author":"Roulois","year":"2015","journal-title":"Cell"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1002\/cam4.1087","article-title":"The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer","volume":"6","author":"Imai","year":"2017","journal-title":"Cancer Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1158\/1078-0432.498.11.2","article-title":"Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma","volume":"11","author":"Ryschich","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1111\/cas.14514","article-title":"Expression of classical human leukocyte antigen class I antigens, HLA-E and HLA-G, is adversely prognostic in pancreatic cancer patients","volume":"111","author":"Hiraoka","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1126\/science.aao4572","article-title":"Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy","volume":"359","author":"Chowell","year":"2018","journal-title":"Science"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41568-019-0116-x","article-title":"The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy","volume":"19","author":"Havel","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Kabacaoglu, D., Ciecielski, K.J., Ruess, D.A., and Algul, H. (2018). Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01878"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1053\/j.gastro.2018.12.038","article-title":"Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities","volume":"156","author":"Balachandran","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.gande.2025.05.004","article-title":"Identification of key genes and pathways in the following pancreatic ductal adenocarcinoma (PDAC) using integrated bioinformatics analysis","volume":"3","author":"Shukla","year":"2025","journal-title":"Gastroenterol. Endosc."},{"key":"ref_162","first-page":"3751","article-title":"Identification of key pathways and candidate genes in pancreatic ductal adenocarcinoma using bioinformatics analysis","volume":"17","author":"He","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"103897","DOI":"10.1016\/j.ebiom.2022.103897","article-title":"Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer","volume":"77","author":"Zhang","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41575-019-0245-4","article-title":"Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer","volume":"17","author":"Buscail","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Zhang, H., Liao, X., and Tsai, H.I. (2023). KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1147676"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Shen, H., Lundy, J., Strickland, A.H., Harris, M., Swan, M., Desmond, C., Jenkins, B.J., and Croagh, D. (2022). KRAS G12D Mutation Subtype in Pancreatic Ductal Adenocarcinoma: Does It Influence Prognosis or Stage of Disease at Presentation?. Cells, 11.","DOI":"10.3390\/cells11193175"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"e2453588","DOI":"10.1001\/jamanetworkopen.2024.53588","article-title":"KRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma","volume":"8","author":"Norton","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41698-024-00505-0","article-title":"Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma","volume":"8","author":"Yousef","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Christopher, B.N., Golick, L., Basar, A., Reyes, L., Robinson, R.M., Angerstein, A.O., Krieg, C., Hobbs, G.A., Guttridge, D.C., and O\u2019Bryan, J.P. (2025). Modulating the CXCR2 Signaling Axis Using Engineered Chemokine Fusion Proteins to Disrupt Myeloid Cell Infiltration in Pancreatic Cancer. Biomolecules, 15.","DOI":"10.3390\/biom15050645"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1158\/2326-6066.CIR-15-0241","article-title":"Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells","volume":"4","author":"Zdanov","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00262-021-03019-x","article-title":"Identification of LIPH as an unfavorable biomarkers correlated with immune suppression or evasion in pancreatic cancer based on RNA-seq","volume":"71","author":"Zhuang","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Krupa, K., Fudalej, M., Wloszek, E., Miski, H., Badowska-Kozakiewicz, A.M., Mekal, D., Budzik, M.P., Czerw, A., and Deptala, A. (2025). Treatment of KRAS-Mutated Pancreatic Cancer: New Hope for the Patients?. Cancers, 17.","DOI":"10.3390\/cancers17152453"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"17450","DOI":"10.1073\/pnas.1901765116","article-title":"ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer","volume":"116","author":"Hashimoto","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/j.jcmgh.2022.02.016","article-title":"Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming","volume":"13","author":"Donahue","year":"2022","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1172\/JCI59227","article-title":"Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice","volume":"122","author":"Collins","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cell.2012.01.058","article-title":"Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism","volume":"149","author":"Ying","year":"2012","journal-title":"Cell"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/j.devcel.2023.07.025","article-title":"Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8(+) T cells","volume":"58","author":"Mahadevan","year":"2023","journal-title":"Dev. Cell"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1158\/2159-8290.CD-22-1066","article-title":"Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer","volume":"13","author":"Kemp","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1158\/2159-8290.CD-24-1475","article-title":"T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma","volume":"15","author":"Orlen","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1053\/j.gastro.2021.04.064","article-title":"TGF-beta Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer","volume":"161","author":"Gough","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1016\/0016-5085(93)91084-U","article-title":"Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival","volume":"105","author":"Friess","year":"1993","journal-title":"Gastroenterology"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Principe, D.R., Timbers, K.E., Atia, L.G., Koch, R.M., and Rana, A. (2021). TGFbeta Signaling in the Pancreatic Tumor Microenvironment. Cancers, 13.","DOI":"10.3390\/cancers13205086"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1210\/me.2015-1102","article-title":"Insights Into SMAD4 Loss in Pancreatic Cancer From Inducible Restoration of TGF-beta Signaling","volume":"29","author":"Fullerton","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","article-title":"TGF-beta signaling in health, disease, and therapeutics","volume":"9","author":"Deng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.cytogfr.2026.01.005","article-title":"TGF-beta-YY1 signaling as a key driver of immune evasion in pancreatic cancer: Therapeutic implications","volume":"88","author":"Ho","year":"2026","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s13402-021-00594-0","article-title":"Role of TGF-beta in pancreatic ductal adenocarcinoma progression and PD-L1 ex-pression","volume":"44","author":"Hussain","year":"2021","journal-title":"Cell Oncol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.phrs.2019.01.038","article-title":"Transforming growth factor-beta in pancreatic diseases: Mechanisms and therapeutic potential","volume":"142","author":"Zhou","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s12029-018-00195-5","article-title":"TGF-beta Inhibitors in Metastatic Pancreatic Ductal Adenocarcinoma","volume":"50","author":"Alvarez","year":"2019","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"di Miceli, N., Baioni, C., Barbieri, L., Danielli, D., Sala, E., Salvioni, L., Garbujo, S., Colombo, M., Prosperi, D., and Innocenti, M. (2024). TGF-beta Signaling Loop in Pancreatic Ductal Adenocarcinoma Activates Fibroblasts and Increases Tumor Cell Aggressiveness. Cancers, 16.","DOI":"10.3390\/cancers16213705"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11605-021-05087-x","article-title":"TGF-beta Alters the Proportion of Infiltrating Immune Cells in a Pancreatic Ductal Adenocarcinoma","volume":"26","author":"Chaib","year":"2022","journal-title":"J. Gastrointest. Surg."},{"key":"ref_191","first-page":"925s","article-title":"Systemic and local immunosuppression in pancreatic cancer patients","volume":"7","author":"Voss","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"3742","DOI":"10.1158\/1538-7445.AM2016-3742","article-title":"Abstract 3742: Treatment with trabedersen, an anti-TGF-beta 2 antisense, primed tumors to subsequent chemotherapies","volume":"76","author":"Hwang","year":"2016","journal-title":"Cancer Res."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"109578","DOI":"10.1016\/j.celrep.2021.109578","article-title":"Gain-of-function p53(R172H) mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy","volume":"36","author":"Siolas","year":"2021","journal-title":"Cell Rep."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"e2025631118","DOI":"10.1073\/pnas.2025631118","article-title":"TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment","volume":"118","author":"Maddalena","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"e2204610119","DOI":"10.1073\/pnas.2204610119","article-title":"Author correction: Mutant p53 drives metastasis and overcomes growth arrest\/senescence in pancreatic cancer","volume":"119","author":"Morton","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_196","doi-asserted-by":"crossref","unstructured":"Klemke, L., Fehlau, C.F., Winkler, N., Toboll, F., Singh, S.K., Moll, U.M., and Schulz-Heddergott, R. (2021). The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.642603"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"e2200570","DOI":"10.1200\/PO.22.00570","article-title":"TP53 Gain-of-Function and Non-Gain-of-Function Mutations Are Associated With Differential Prognosis in Advanced Pancreatic Ductal Adenocarcinoma","volume":"7","author":"Pan","year":"2023","journal-title":"JCO Precis. Oncol."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1002\/jso.70060","article-title":"P53 Function Status Correlates With Overall Survival in Patients With Resected Pancreatic Cancer","volume":"132","author":"Chen","year":"2025","journal-title":"J. Surg. Oncol."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1016\/j.immuni.2025.06.005","article-title":"Mutant p53 exploits enhancers to elevate immunosuppressive chemokine expression and impair immune checkpoint inhibitors in pancreatic cancer","volume":"58","author":"Mahat","year":"2025","journal-title":"Immunity"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/18\/1599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:13:08Z","timestamp":1789359188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/18\/1599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":199,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biology15181599"],"URL":"https:\/\/doi.org\/10.3390\/biology15181599","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}