{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T07:41:32Z","timestamp":1794210092106,"version":"4.8.0"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by profound lethality, aggressive local invasion, dismal prognosis, and significant resistance to existing therapies. Two critical biological features underpin the challenges in treating PDAC: extensive perineural invasion (PNI), the process by which cancer cells infiltrate and migrate along nerves, and a profoundly immunosuppressive, or \u201ccold,\u201d tumor microenvironment (TME). PNI is not only a primary route for local tumor dissemination and recurrence but also a major contributor to the severe pain often experienced by patients. Concurrently, the PDAC TME is typified by a dense desmoplastic stroma, hypoxia, and an abundance of immunosuppressive cells\u2014including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)\u2014while lacking sufficient infiltration of effector T cells, rendering it largely unresponsive to immunotherapies like checkpoint inhibitors. Although historically studied as separate entities, accumulating evidence reveals a deep-seated and complex bidirectional crosstalk between the neural components involved in PNI and the immune and stromal cells constituting the TME. Key cellular mediators, such as CAFs and TAMs, and shared signaling pathways, including the CXCL12\/CXCR4 axis, TGF-\u03b2 signaling, and neurotrophin pathways (e.g., NGF\/TrkA), appear to act as critical nodes, coordinating the progression of PNI while simultaneously shaping and maintaining the immunosuppressive TME. This review synthesizes the current understanding of these intricate neuro-immune interactions in PDAC. We delineate the molecular and cellular mechanisms governing this crosstalk and explore how targeting these shared regulatory networks presents novel therapeutic opportunities, potentially disrupting PNI while concurrently \u201cheating\u201d the cold TME to overcome immunotherapy resistance. Elucidating this interplay is crucial not only for a deeper comprehension of PDAC\u2019s invasive and metastatic mechanisms but also for uncovering new therapeutic vulnerabilities to improve patient outcomes.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1650117","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T04:14:27Z","timestamp":1755663267000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Perineural invasion and the \u201ccold\u201d tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities"],"prefix":"10.3389","volume":"16","author":[{"given":"Jianbiao","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanjiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193068","article-title":"Pancreatic ductal adenocarcinoma: molecular pathology and predictive biomarkers","volume":"11","author":"Taherian","year":"2022","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2023.05.03","article-title":"Epidemiology of pancreatic cancer: New version, new vision","volume":"35","author":"Luo","year":"2023","journal-title":"Chin J Cancer Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1386699","article-title":"Pancreatic ductal adenocarcinoma: the latest on diagnosis, molecular profiling, and systemic treatments","volume":"14","author":"Bugazia","year":"2024","journal-title":"Front Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.050624","article-title":"Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back","volume":"17","author":"Lloyd","year":"2024","journal-title":"Dis Model Mech"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1309738","article-title":"Crosstalk of nervous and immune systems in pancreatic cancer","volume":"11","author":"Huang","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.992927","article-title":"The connection between innervation and metabolic rearrangements in pancreatic cancer through serine","volume":"12","author":"Dong","year":"2022","journal-title":"Front Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16132438","article-title":"Decoding the intricate landscape of pancreatic cancer: insights into tumor biology, microenvironment, and therapeutic interventions","volume":"16","author":"Argentiero","year":"2024","journal-title":"Cancers"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1421067","article-title":"Hallmarks of perineural invasion in pancreatic ductal adenocarcinoma: new biological dimensions","volume":"14","author":"Sun","year":"2024","journal-title":"Front Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v27.i39.6527","article-title":"Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities","volume":"27","author":"Jain","year":"2021","journal-title":"World J Gastroenterol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2021.02.003","article-title":"KRAS mutation in pancreatic cancer","volume":"48","author":"Luo","year":"2021","journal-title":"Semin Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13045-024-01561-6","article-title":"Current and future immunotherapeutic approaches in pancreatic cancer treatment","volume":"17","author":"Farhangnia","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17050852","article-title":"Spatial transcriptomics reveals novel mechanisms involved in perineural invasion in pancreatic ductal adenocarcinomas","volume":"17","author":"Lakis","year":"2025","journal-title":"Cancers"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/cancers2031513","article-title":"Neural invasion in pancreatic cancer: the past, present and future","volume":"2","author":"Demir","year":"2010","journal-title":"Cancers"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14163994","article-title":"Heterogeneity of cancer-associated fibroblasts and the tumor immune microenvironment in pancreatic cancer","volume":"14","author":"Shinkawa","year":"2022","journal-title":"Cancers"},{"key":"B15","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1158\/1535-7163.Mct-24-0311","article-title":"Looking beyond checkpoint inhibitor monotherapy: uncovering new frontiers for pancreatic cancer immunotherapy","volume":"24","author":"Giurini","year":"2025","journal-title":"Mol Cancer Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070893","article-title":"Nerves and pancreatic cancer: new insights into a dangerous relationship","volume":"11","author":"Gasparini","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13030609","article-title":"Neuroimmune interactions in pancreatic cancer","volume":"13","author":"Cheng","year":"2025","journal-title":"Biomedicines"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.04.010","article-title":"Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve","volume":"200","author":"Jurcak","year":"2019","journal-title":"Pharmacol Ther"},{"key":"B19","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12943-021-01428-1","article-title":"Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives","volume":"20","author":"Mao","year":"2021","journal-title":"Mol Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12188","article-title":"Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma","volume":"41","author":"Li","year":"2021","journal-title":"Cancer Commun (Lond)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1154581","article-title":"The role of CXCL12 axis in pancreatic cancer: New biomarkers and potential targets","volume":"13","author":"Roberto","year":"2023","journal-title":"Front Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/s41388-020-01578-4","article-title":"Nerve fibers in the tumor microenvironment in neurotropic cancer-pancreatic cancer and cholangiocarcinoma","volume":"40","author":"Tan","year":"2021","journal-title":"Oncogene"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-023-01082-1","article-title":"Crosstalk between peripheral innervation and pancreatic ductal adenocarcinoma","volume":"39","author":"Ni","year":"2023","journal-title":"Neurosci Bull"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14235793","article-title":"Perineural invasion in pancreatic ductal adenocarcinoma: from molecules towards drugs of clinical relevance","volume":"14","author":"Selvaggi","year":"2022","journal-title":"Cancers"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.217515","article-title":"Exploring the biological mechanism and clinical value of perineural invasion in pancreatic cancer","volume":"613","author":"Yuan","year":"2025","journal-title":"Cancer Lett"},{"key":"B26","first-page":"1","article-title":"Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche","volume":"9","author":"Chen","year":"2019","journal-title":"Am J Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2024.13233","article-title":"Pancreatic stellate cells: Key players in pancreatic health and diseases (Review)","volume":"30","author":"Wang","year":"2024","journal-title":"Mol Med Rep"},{"key":"B28","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12943-024-01965-5","article-title":"Activation of the PI3K\/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib","volume":"23","author":"Ge","year":"2024","journal-title":"Mol Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-17-1612","article-title":"Inflammatory monocytes promote perineural invasion via CCL2-mediated recruitment and cathepsin B expression","volume":"77","author":"Bakst","year":"2017","journal-title":"Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s13046-019-1110-6","article-title":"Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology","volume":"38","author":"Nissen","year":"2019","journal-title":"J Exp Clin Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-21-1690","article-title":"Reprogrammed schwann cells organize into dynamic tracks that promote pancreatic cancer invasion","volume":"12","author":"Deborde","year":"2022","journal-title":"Cancer Discov"},{"key":"B32","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12943-019-0966-6","article-title":"TAMing pancreatic cancer: combat with a double edged sword","volume":"18","author":"Lankadasari","year":"2019","journal-title":"Mol Cancer"},{"key":"B33","doi-asserted-by":"publisher","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":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13184594","article-title":"Perineural invasion and associated pain transmission in pancreatic cancer","volume":"13","author":"Wang","year":"2021","journal-title":"Cancers"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216689","article-title":"Schwann cells in pancreatic cancer: Unraveling their multifaceted roles in tumorigenesis and neural interactions","volume":"587","author":"Cai","year":"2024","journal-title":"Cancer Lett"},{"key":"B36","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1053\/j.gastro.2019.05.065","article-title":"Axon guidance molecules promote perineural invasion and metastasis of orthotopic pancreatic tumors in mice","volume":"157","author":"Jurcak","year":"2019","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16713","article-title":"CXCL12\/CXCR4 facilitates perineural invasion via induction of the Twist\/S100A4 axis in salivary adenoid cystic carcinoma","volume":"25","author":"Zhang","year":"2021","journal-title":"J Cell Mol Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cells11213340","article-title":"CXCR4-CXCL12-CXCR7 and PD-1\/PD-L1 in pancreatic cancer: CXCL12 predicts survival of radically resected patients","volume":"11","author":"D'Alterio","year":"2022","journal-title":"Cells"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2147\/ijn.S504503","article-title":"Extensive review of nanomedicine strategies targeting the tumor microenvironment in PDAC","volume":"20","author":"Liu","year":"2025","journal-title":"Int J Nanomedicine"},{"key":"B40","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13045-020-01030-w","article-title":"Targeting hypoxic tumor microenvironment in pancreatic cancer","volume":"14","author":"Tao","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/s41392-021-00670-9","article-title":"Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25116003","article-title":"CAFs-associated genes (CAFGs) in pancreatic ductal adenocarcinoma (PDAC) and novel therapeutic strategy","volume":"25","author":"Yamashita","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s12943-023-01860-5","article-title":"Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials","volume":"22","author":"Zhang","year":"2023","journal-title":"Mol Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41392-021-00484-9","article-title":"Targeting tumor-associated macrophages to synergize tumor immunotherapy","volume":"6","author":"Xiang","year":"2021","journal-title":"Signal transduction targeted Ther"},{"key":"B45","doi-asserted-by":"publisher","first-page":"104982","DOI":"10.1016\/j.yexmp.2025.104982","article-title":"Revisiting TAM polarization: beyond M1-and M2-type TAM toward clinical precision in macrophage-targeted therapy","volume":"143","author":"Wang","year":"2025","journal-title":"Exp Mol Pathol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s13045-024-01559-0","article-title":"Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy","volume":"17","author":"Toledo","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1573522","article-title":"Phenotypic heterogeneity and tumor immune microenvironment directed therapeutic strategies in pancreatic ductal adenocarcinoma","volume":"16","author":"Ramesh","year":"2025","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1295684","article-title":"Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs","volume":"14","author":"Shao","year":"2023","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1097\/mpa.0000000000001621","article-title":"T-cell immunity in pancreatic cancer","volume":"49","author":"Ajina","year":"2020","journal-title":"Pancreas"},{"key":"B50","doi-asserted-by":"publisher","first-page":"217350","DOI":"10.1016\/j.canlet.2024.217350","article-title":"Frontiers in pancreatic cancer on biomarkers, microenvironment, and immunotherapy","volume":"610","author":"Yu","year":"2025","journal-title":"Cancer Lett"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8091472","article-title":"Strategies in developing immunotherapy for pancreatic cancer: recognizing and correcting multiple immune \"Defects\" in the tumor microenvironment","volume":"8","author":"Upadhrasta","year":"2019","journal-title":"J Clin Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13061297","article-title":"LAG-3-expressing tumor-infiltrating T cells are associated with reduced disease-free survival in pancreatic cancer","volume":"13","author":"Seifert","year":"2021","journal-title":"Cancers"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2025.123280","article-title":"Stromal fibrin shapes immune infiltration landscape of pancreatic ductal adenocarcinoma","volume":"320","author":"Karim","year":"2025","journal-title":"Biomaterials"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.951019","article-title":"The immunoregulation effect of tumor microenvironment in pancreatic ductal adenocarcinoma","volume":"12","author":"Zhang","year":"2022","journal-title":"Front Oncol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082274","article-title":"Mechanisms of T-cell exhaustion in pancreatic cancer","volume":"12","author":"Saka","year":"2020","journal-title":"Cancers"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10010006","article-title":"Immune evasion in pancreatic cancer: from mechanisms to therapy","volume":"10","author":"Martinez-Bosch","year":"2018","journal-title":"Cancers"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14194880","article-title":"Multiphasic heterogeneity of fibroblasts in the microenvironment of pancreatic ductal adenocarcinoma: dissection and the sum of the dynamics","volume":"14","author":"Ijichi","year":"2022","journal-title":"Cancers"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.688953","article-title":"Shedding light on the role of neurotransmitters in the microenvironment of pancreatic cancer","volume":"9","author":"Liang","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/s41419-019-1385-8","article-title":"Neurotrophins and their involvement in digestive cancers","volume":"10","author":"Blondy","year":"2019","journal-title":"Cell Death Dis"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1499414","article-title":"NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes","volume":"15","author":"Trentini","year":"2024","journal-title":"Front Pharmacol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1097\/mpa.0000000000001090","article-title":"Systemic depletion of nerve growth factor inhibits disease progression in a genetically engineered model of pancreatic ductal adenocarcinoma","volume":"47","author":"Saloman","year":"2018","journal-title":"Pancreas"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16101875","article-title":"The crosstalk between nerves and cancer-A poorly understood phenomenon and new possibilities","volume":"16","author":"Benzaquen","year":"2024","journal-title":"Cancers"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-20-2793","article-title":"Cancer-associated neurogenesis and nerve-cancer cross-talk","volume":"81","author":"Silverman","year":"2021","journal-title":"Cancer Res"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1101\/2023.06.26.546629","article-title":"Pancreatic tumor-derived extracellular vesicles stimulate schwann cell phenotype indicative of perineural invasion via IL-8 signaling","volume":"4","author":"Gregory","year":"2023","journal-title":"bioRxiv: preprint server Biol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/5775696","article-title":"The role of TAMs in tumor microenvironment and new research progress","volume":"2022","author":"Feng","year":"2022","journal-title":"Stem Cells Int"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1142838","article-title":"The immunomodulatory role of IDO1-Kynurenine-NAD(+) pathway in switching cold tumor microenvironment in PDAC","volume":"13","author":"Anu","year":"2023","journal-title":"Front Oncol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/9681698","article-title":"CXCL12 and its isoforms: different roles in pancreatic cancer","volume":"2019","author":"Righetti","year":"2019","journal-title":"J Oncol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1287459","article-title":"Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target","volume":"15","author":"Hartupee","year":"2024","journal-title":"Front Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.024","article-title":"Transforming growth factor-\u03b2 Signaling in immunity and cancer","volume":"50","author":"Batlle","year":"2019","journal-title":"Immunity"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3390\/jcm6010005","article-title":"The TGF-\u03b2\/smad4 signaling pathway in pancreatic carcinogenesis and its clinical significance","volume":"6","author":"Ahmed","year":"2017","journal-title":"J Clin Med"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-021-00594-0","article-title":"Role of TGF-\u03b2 in pancreatic ductal adenocarcinoma progression and PD-L1 expression","volume":"44","author":"Hussain","year":"2021","journal-title":"Cell Oncol (Dordr)"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0165586","article-title":"Blocking nerve growth factor signaling reduces the neural invasion potential of pancreatic cancer cells","volume":"11","author":"Bapat","year":"2016","journal-title":"PloS One"},{"key":"B73","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.3390\/cancers16101875","article-title":"The crosstalk between nerves and cancer\u2014A poorly understood phenomenon and new possibilities","volume":"16","author":"Benzaquen","year":"2024","journal-title":"Cancers (Basel)"},{"key":"B74","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1046\/j.1469-7580.2003.00203.x","article-title":"Neurotrophins and the immune system","volume":"203","author":"Vega","year":"2003","journal-title":"J Anat"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-031621-024600","article-title":"Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance","volume":"18","author":"Sherman","year":"2023","journal-title":"Annu Rev Pathol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.2147\/ijn.S451151","article-title":"Nano-drug delivery systems targeting CAFs: A promising treatment for pancreatic cancer","volume":"19","author":"Wang","year":"2024","journal-title":"Int J Nanomedicine"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.6004\/jadpro.2020.11.7.4","article-title":"Pancreatic ductal adenocarcinoma: characteristics of tumor microenvironment and barriers to treatment","volume":"11","author":"Vega","year":"2020","journal-title":"J Adv Pract Oncol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010061","article-title":"Cancer-associated fibroblast diversity shapes tumor metabolism in pancreatic cancer","volume":"15","author":"Peiffer","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202264","article-title":"Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition","volume":"13","author":"Xiong","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B80","doi-asserted-by":"publisher","first-page":"1","DOI":"10.21037\/apc.2019.06.04","article-title":"Cellular crosstalk mediating immune evasion in pancreatic cancer microenvironment","volume":"2","author":"Gao","year":"2019","journal-title":"Ann Pancreatic Cancer"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-22-0275","article-title":"Multi-omic characterization of pancreatic ductal adenocarcinoma relates CXCR4 mRNA expression levels to potential clinical targets","volume":"28","author":"Kocher","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v28.i27.3297","article-title":"Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy","volume":"28","author":"Smith","year":"2022","journal-title":"World J Gastroenterol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-15-1293","article-title":"TGF\u03b2 Signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis","volume":"76","author":"Principe","year":"2016","journal-title":"Cancer Res"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13215318","article-title":"Targeting tumor-associated macrophages in cancer immunotherapy","volume":"13","author":"Petty","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.12.007","article-title":"The CXCL12-CXCR4\/CXCR7 axis as a mechanism of immune resistance in gastrointestinal Malignancies","volume":"65","author":"Daniel","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0880-x","article-title":"BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial","volume":"26","author":"Bockorny","year":"2020","journal-title":"Nat Med"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002068","article-title":"Safety and activity of the TGF\u03b2 receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer","volume":"9","author":"Melisi","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14215246","article-title":"Neural component of the tumor microenvironment in pancreatic ductal adenocarcinoma","volume":"14","author":"Gola","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B89","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.ccell.2017.11.007","article-title":"\u03b22 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer","volume":"33","author":"Renz","year":"2018","journal-title":"Cancer Cell"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1111\/cas.16443","article-title":"Targeting cancer-associated fibroblasts: eliminate or reprogram","volume":"116","author":"Yamazaki","year":"2025","journal-title":"Cancer Sci"},{"key":"B91","doi-asserted-by":"publisher","first-page":"4308","DOI":"10.1038\/s41467-022-31928-7","article-title":"Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement","volume":"13","author":"Liu","year":"2022","journal-title":"Nat Commun"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2024.2357802","article-title":"The trend toward more target therapy in pancreatic ductal adenocarcinoma","volume":"24","author":"Deiana","year":"2024","journal-title":"Expert Rev Anticancer Ther"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5245034","article-title":"Combinatorial approach to improve cancer immunotherapy: rational drug design strategy to simultaneously hit multiple targets to kill tumor cells and to activate the immune system","volume":"2019","author":"Joshi","year":"2019","journal-title":"J Oncol"},{"key":"B94","doi-asserted-by":"publisher","first-page":"1","DOI":"10.21037\/dmr-24-2","article-title":"Recent advances in immunotherapy for pancreatic cancer: a narrative review","volume":"7","author":"Firoozan","year":"2024","journal-title":"Digestive Med Res"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01813-y","article-title":"Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma","volume":"22","author":"Gautam","year":"2023","journal-title":"Mol Cancer"},{"key":"B96","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s12943-024-02032-9","article-title":"A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy","volume":"23","author":"Li","year":"2024","journal-title":"Mol Cancer"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1615760","article-title":"Unleashing the power of CAR-M therapy in solid tumors: a comprehensive review","volume":"16","author":"Morva","year":"2025","journal-title":"Front Immunol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s40164-024-00549-9","article-title":"The next frontier in immunotherapy: potential and challenges of CAR-macrophages","volume":"13","author":"Li","year":"2024","journal-title":"Exp Hematol Oncol"},{"key":"B99","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41586-024-08508-4","article-title":"RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer","volume":"2","author":"Sethna","year":"2025","journal-title":"Nature"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-010124","article-title":"Pancreatic cancer is feeling the heat","volume":"12","author":"Maru","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B101","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s43018-022-00500-z","article-title":"Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1\/CXCR2 results in antitumor immunity and durable response in pancreatic cancer","volume":"4","author":"Gulhati","year":"2023","journal-title":"Nat Cancer"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8091472","article-title":"Strategies in developing immunotherapy for pancreatic cancer: recognizing and correcting multiple immune \u201cDefects\u201d in the tumor microenvironment","volume":"8","author":"Upadhrasta","year":"2019","journal-title":"JCM"},{"key":"B103","doi-asserted-by":"publisher","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":"B104","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17040606","article-title":"Challenges and opportunities for the clinical application of the combination of immune-checkpoint inhibitors and radiation therapy in the treatment of advanced pancreatic cancer","volume":"17","author":"Kanai","year":"2025","journal-title":"Cancers (Basel)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1650117\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T04:14:29Z","timestamp":1755663269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1650117\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,20]]},"references-count":104,"alternative-id":["10.3389\/fimmu.2025.1650117"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1650117","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,20]]},"article-number":"1650117"}}