Decoding the pancreatic cancer microenvironment: The multifaceted regulation of microRNAs

Abstract

Pancreatic cancer (PC) is an extremely deadly type of cancer, and the 5-year survival rate remains less than 10%. The tumour microenvironment (TME) affects the occurrence, progression and treatment outcomes of PC. MicroRNAs (miRNAs) are essential to regulate PC TME. This review delves into the different roles of miRNAs in the PC TME, including exosome communication, angiogenesis, interactions with cancer-associated fibroblasts, the immunological and neuronal microenvironments and metabolic reprogramming. However, research on the complex regulatory networks and synergistic effects of miRNAs in the TME is still insufficient, and their clinical translation and application face challenges. This review summarised the activities of miRNAs in the PC TME, guiding future research and therapeutic strategies involving miRNAs in PC. Future studies should integrate advanced technologies to decode the spatiotemporal dynamics of miRNA regulation within the TME and develop optimised nanodelivery systems for stable and targeted miRNA delivery, advancing clinical applications in PC treatment.

Keywords

exosome / immune microenvironment / miRNA / PC / tumour microenvironment

References

[1] Shah A, Ganguly K, Rauth S, et al. Unveiling the resistance to therapies in pancreatic ductal adenocarcinoma. Drug Resist Updat. 2024; 77: 101146.

[2] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74: 12-49.

[3] Adamska A, Domenichini A, Falasca M. Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci. 2017; 18.

[4] Mao X, Xu J, Wang W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021; 20: 131.

[5] Goliwas KF, Deshane JS, Elmets CA, Athar M. Moving immune therapy forward targeting TME. Physiol Rev. 2021; 101: 417-425.

[6] Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020; 30: R921-R925.

[7] Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019; 79: 4557-4566.

[8] Sherman MH, Beatty GL. Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance. Annu Rev Pathol. 2023; 18: 123-148.

[9] Yu B, Shao S, Ma W. Frontiers in pancreatic cancer on biomarkers, microenvironment, and immunotherapy. Cancer Lett. 2025; 610: 217350.

[10] Ferragut Cardoso AP, Banerjee M, Nail AN, Lykoudi A, States JC. miRNA dysregulation is an emerging modulator of genomic instability. Semin Cancer Biol. 2021; 76: 120-131.

[11] Zhang J, Liu L, Xu T, et al. Time to infer miRNA sponge modules. Wiley Interdiscip Rev RNA. 2022; 13: e1686.

[12] Pal A, Ojha A, Ju J. Functional and potential therapeutic implication of microRNAs in pancreatic cancer. Int J Mol Sci. 2023: 24.

[13] He B, Zhao Z, Cai Q, et al. miRNA-based biomarkers, therapies, and resistance in cancer. Int J Biol Sci. 2020; 16: 2628-2647.

[14] Li B, Cao Y, Sun M, Feng H. Expression, regulation, and function of exosome-derived miRNAs in cancer progression and therapy. FASEB J. 2021; 35: e21916.

[15] Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer. 2024; 23: 170.

[16] Schoepp M, Strose AJ, Haier J. Dysregulation of miRNA expression in cancer associated fibroblasts (CAFs) and its consequences on the tumor microenvironment. Cancers (Basel). 2017: 9.

[17] Xing Y, Ruan G, Ni H, et al. Tumor Immune microenvironment and its related miRNAs in tumor progression. Front Immunol. 2021; 12: 624725.

[18] Han L, Chen S, Luan Z, et al. Immune function of colon cancer associated miRNA and target genes. Front Immunol. 2023; 14: 1203070.

[19] Godinez-Rubi M, Ortuno-Sahagun D. miR-615 fine-tunes growth and development and has a role in cancer and in neural repair. Cells. 2020: 9.

[20] Marengo B, Pulliero A, Izzotti A, Domenicotti C. miRNA regulation of glutathione homeostasis in cancer initiation, progression and therapy resistance. Microrna. 2020; 9: 187-197.

[21] Ji J, Jin D, Xu M, et al. AKR1B1 promotes pancreatic cancer metastasis by regulating lysosome-guided exosome secretion. Nano Research. 2022; 15: 5279-5294.

[22] Xu M, Ji J, Jin D, et al. The biogenesis and secretion of exosomes and multivesicular bodies (MVBs): intercellular shuttles and implications in human diseases. Genes Dis. 2023; 10: 1894-1907.

[23] Huang M, Ji J, Xu X, et al. Known and unknown: exosome secretion in tumor microenvironment needs more exploration. Genes Dis. 2025; 12: 101175.

[24] Goto T, Fujiya M, Konishi H, et al. An elevated expression of serum exosomal microRNA-191, - 21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker. BMC Cancer. 2018; 18: 116.

[25] Xu YF, Hannafon BN, Zhao YD, Postier RG, Ding WQ. Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer. Oncotarget. 2017; 8: 77028-77040.

[26] Verel-Yilmaz Y, Fernandez JP, Schafer A, et al. Extracellular vesicle-based detection of pancreatic cancer. Front Cell Dev Biol. 2021; 9: 697939.

[27] Xu X, Bhandari K, Xu C, Morris K, Ding WQ. miR-18a and miR-106a signatures in plasma small EVs are promising biomarkers for early detection of pancreatic ductal adenocarcinoma. Int J Mol Sci. 2023: 24.

[28] Yoshizawa N, Sugimoto K, Tameda M, et al. miR-3940-5p/miR-8069 ratio in urine exosomes is a novel diagnostic biomarker for pancreatic ductal adenocarcinoma. Oncol Lett. 2020; 19: 2677-2684.

[29] Nesteruk K, Levink IJM, de Vries E, et al. Extracellular vesicle-derived microRNAs in pancreatic juice as biomarkers for detection of pancreatic ductal adenocarcinoma. Pancreatology. 2022; 22: 626-635.

[30] Taniguchi T, Ideno N, Araki T, et al. MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma. DEN Open. 2024; 4: e333.

[31] Wang L, Wu J, Ye N, et al. Plasma-derived exosome MiR-19b acts as a diagnostic marker for pancreatic cancer. Front Oncol. 2021; 11: 739111.

[32] Wu L, Zhou WB, Zhou J, et al. Circulating exosomal microRNAs as novel potential detection biomarkers in pancreatic cancer. Oncol Lett. 2020; 20: 1432-1440.

[33] Shao H, Zhang Y, Yan J, et al. Upregulated MicroRNA-483-3p is an early event in pancreatic ductal adenocarcinoma (PDAC) and as a powerful liquid biopsy biomarker in PDAC. Onco Targets Ther. 2021; 14: 2163-2175.

[34] Marin AM, Mattar SB, Amatuzzi RF, et al. Plasma exosome-derived microRNAs as potential diagnostic and prognostic biomarkers in brazilian pancreatic cancer patients. Biomolecules. 2022: 12.

[35] Tang R, Zhang Z, Xu J, et al. Integration of single-nucleus and exosome RNA sequencing dissected inter-cellular communication and biomarkers in pancreatic ductal adenocarcinoma. Comput Struct Biotechnol J. 2024; 23: 1689-1704.

[36] Kim YG, Park J, Park EY, Kim SM, Lee SY. Analysis of MicroRNA signature differentially expressed in pancreatic islet cells treated with pancreatic cancer-derived exosomes. Int J Mol Sci. 2023: 24.

[37] Schofield AL, Brown JP, Brown J, et al. Systems analysis of miRNA biomarkers to inform drug safety. Arch Toxicol. 2021; 95: 3475-3495.

[38] Aveta A, Cilio S, Contieri R, et al. Urinary microRNAs as biomarkers of urological cancers: a systematic review. Int J Mol Sci. 2023: 24.

[39] Tarasiuk A, Mackiewicz T, Malecka-Panas E, Fichna J. Biomarkers for early detection of pancreatic cancer—miRNAs as a potential diagnostic and therapeutic tool?. Cancer Biol Ther. 2021; 22: 347-356.

[40] He D, Wang H, Ho SL, et al. Total internal reflection-based single-vesicle in situ quantitative and stoichiometric analysis of tumor-derived exosomal microRNAs for diagnosis and treatment monitoring. Theranostics. 2019; 9: 4494-4507.

[41] Madhavan B, Yue S, Galli U, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer. 2015; 136: 2616-2627.

[42] Sun Z, Shi K, Yang S, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer. 2018; 17: 147.

[43] Li Z, Tao Y, Wang X, et al. Tumor-secreted exosomal miR-222 promotes tumor progression via regulating P27 expression and re-localization in pancreatic cancer. Cell Physiol Biochem. 2018; 51: 610-629.

[44] Yu Z, Zhao S, Wang L, Wang J, Zhou J. miRNA-339-5p Plays an important role in invasion and migration of pancreatic cancer cells. Med Sci Monit. 2019; 25: 7509-7517.

[45] Masamune A, Yoshida N, Hamada S, Takikawa T, Nabeshima T, Shimosegawa T. Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. Biochem Biophys Res Commun. 2018; 495: 71-77.

[46] Patel GK, Khan MA, Bhardwaj A, et al. Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK. Br J Cancer. 2017; 116: 609-619.

[47] Qin C, Zhao B, Wang Y, et al. Extracellular vesicles miR-31-5p promotes pancreatic cancer chemoresistance via regulating LATS2-Hippo pathway and promoting SPARC secretion from pancreatic stellate cells. J Extracell Vesicles. 2024; 13: e12488.

[48] Lee TY, Tseng CJ, Wang JW, et al. Anti-microRNA-1976 as a novel approach to enhance chemosensitivity in XAF1(+) pancreatic and liver cancer. Biomedicines. 2023: 11.

[49] Ueda H, Takahashi H, Kobayashi S, et al. miR-6855-5p enhances radioresistance and promotes migration of pancreatic cancer by inducing epithelial-mesenchymal transition via suppressing FOXA1: potential of plasma exosomal miR-6855-5p as an indicator of radiosensitivity in patients with pancreatic cancer. Ann Surg Oncol. 2024.

[50] Jiang MJ, Chen YY, Dai JJ, et al. Dying tumor cell-derived exosomal miR-194-5p potentiates survival and repopulation of tumor repopulating cells upon radiotherapy in pancreatic cancer. Mol Cancer. 2020; 19: 68.

[51] Wang L, Li X, Wu J, Tang Q. Pancreatic cancer-derived exosomal miR-Let-7b-5p stimulates insulin resistance in skeletal muscle cells through RNF20/STAT3/FOXO1 axis regulation. Diabetes Metab Syndr Obes. 2023; 16: 3133-3145.

[52] Tien SC, Chang CC, Huang CH, et al. Exosomal miRNA 16-5p/29a-3p from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis. iScience. 2024; 27: 110346.

[53] Pang W, Yao W, Dai X. miRNA 16-5p/29a-3p from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis. Int J Biol Sci. 2021; 17: 3622-3633.

[54] Zhou Y, Zhu Y, Dong X, et al. Exosomes derived from pancreatic cancer cells induce osteoclast differentiation through the miR125a-5p/TNFRSF1B pathway. Onco Targets Ther. 2021; 14: 2727-2739.

[55] Calore F, Londhe P, Fadda P, et al. The TLR7/8/9 antagonist IMO-8503 inhibits cancer-induced cachexia. Cancer Res. 2018; 78: 6680-6690.

[56] Takikawa T, Masamune A, Yoshida N, Hamada S, Kogure T, Shimosegawa T. Exosomes Derived from pancreatic stellate cells: microRNA signature and effects on pancreatic cancer cells. Pancreas. 2017; 46: 19-27.

[57] Ma Q, Wu H, Xiao Y, Liang Z, Liu T. Upregulation of exosomal microRNA‑21 in pancreatic stellate cells promotes pancreatic cancer cell migration and enhances Ras/ERK pathway activity. Int J Oncol. 2020; 56: 1025-1033.

[58] Wu M, Tan X, Liu P, et al. Role of exosomal microRNA-125b-5p in conferring the metastatic phenotype among pancreatic cancer cells with different potential of metastasis. Life Sci. 2020; 255: 117857.

[59] Cao W, Zeng Z, He Z, Lei S. Hypoxic pancreatic stellate cell-derived exosomal mirnas promote proliferation and invasion of pancreatic cancer through the PTEN/AKT pathway. Aging (Albany NY). 2021; 13: 7120-7132.

[60] Cordeiro HG, Azevedo-Martins JM, Faria AVS, et al. Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks. Cell Signal. 2024; 119: 111174.

[61] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285: 1182-1186.

[62] An YF, Pu N, Jia JB, Wang WQ, Liu L. Therapeutic advances targeting tumor angiogenesis in pancreatic cancer: current dilemmas and future directions. Biochim Biophys Acta Rev Cancer. 2023; 1878: 188958.

[63] Luo Q, Wang J, Zhao W, et al. Vasculogenic mimicry in carcinogenesis and clinical applications. J Hematol Oncol. 2020; 13: 19.

[64] Han M, Sun H, Zhou Q, et al. Effects of RNA methylation on tumor angiogenesis and cancer progression. Mol Cancer. 2023; 22: 198.

[65] Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. 2023; 8: 198.

[66] Lou W, Liu J, Gao Y, et al. MicroRNAs in cancer metastasis and angiogenesis. Oncotarget. 2017; 8: 115787-115802.

[67] Zhang X, Tan P, Zhuang Y, Du L. hsa_circRNA_001587 upregulates SLC4A4 expression to inhibit migration, invasion, and angiogenesis of pancreatic cancer cells via binding to microRNA-223. Am J Physiol Gastrointest Liver Physiol. 2020; 319: G703-G717.

[68] Hu H, Zhang Q, Chen W, et al. MicroRNA-301a promotes pancreatic cancer invasion and metastasis through the JAK/STAT3 signaling pathway by targeting SOCS5. Carcinogenesis. 2020; 41: 502-514.

[69] Liu R, Zhang H, Wang X, et al. The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma. Oncotarget. 2015; 6: 43831-43842.

[70] Shang D, Xie C, Hu J, et al. Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2. J Cell Mol Med. 2020; 24: 588-604.

[71] Li X, Xu M, Ding L, Tang J. MiR-27a: a novel biomarker and potential therapeutic target in tumors. J Cancer. 2019; 10: 2836-2848.

[72] Li L, Li B, Chen D, et al. miR-139 and miR-200c regulate pancreatic cancer endothelial cell migration and angiogenesis. Oncol Rep. 2015; 34: 51-58.

[73] Wang L, Mu N, Qu N. Methylation of the miR‑29b‑3p promoter contributes to angiogenesis, invasion, and migration in pancreatic cancer. Oncol Rep. 2021; 45: 65-72.

[74] Sureban SM, May R, Qu D, et al. DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer. PLoS One. 2013; 8: e73940.

[75] Wang L, Yang L, Zhuang T, Shi X. Tumor-derived exosomal mir-29b reduces angiogenesis in pancreatic cancer by silencing ROBO1 and SRGAP2. J Immunol Res. 2022; 2022: 4769385.

[76] Liu A, Huang C, Cai X, Xu J, Yang D. Twist promotes angiogenesis in pancreatic cancer by targeting miR-497/VEGFA axis. Oncotarget. 2016; 7: 25801-25814.

[77] Wang L, Li M, Chen F. microRNA-26a represses pancreatic cancer cell malignant behaviors by targeting E2F7. Discov Oncol. 2021; 12: 55.

[78] Xu D, Yang F, Wu K, et al. Lost miR-141 and upregulated TM4SF1 expressions associate with poor prognosis of pancreatic cancer: regulation of EMT and angiogenesis by miR-141 and TM4SF1 via AKT. Cancer Biol Ther. 2020; 21: 354-363.

[79] Guo R, Gu J, Zhang Z, Wang Y, Gu C. MicroRNA-410 functions as a tumor suppressor by targeting angiotensin II type 1 receptor in pancreatic cancer. IUBMB Life. 2015; 67: 42-53.

[80] Zhu HY, Gao YJ, Wang Y, Liang C, Zhang ZX, Chen Y. LncRNA CRNDE promotes the progression and angiogenesis of pancreatic cancer via miR-451a/CDKN2D axis. Transl Oncol. 2021; 14: 101088.

[81] Liu B, Gong Y, Jiang Q, et al. Hsa_circ_0014784-induced YAP1 promoted the progression of pancreatic cancer by sponging miR-214-3p. Cell Cycle. 2023; 22: 1583-1596.

[82] Fan Y, Shi C, Li T, Kuang T. microRNA-454 shows anti-angiogenic and anti-metastatic activity in pancreatic ductal adenocarcinoma by targeting LRP6. Am J Cancer Res. 2017; 7: 139-147.

[83] Karmakar S, Kaushik G, Nimmakayala R, Rachagani S, Ponnusamy MP, Batra SK. MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention. Semin Cancer Biol. 2019; 54: 63-71.

[84] Chang TC, Wentzel EA, Kent OA, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007; 26: 745-752.

[85] Wang H, Hang C, Ou XL, et al. MiR-145 functions as a tumor suppressor via regulating angiopoietin-2 in pancreatic cancer cells. Cancer Cell Int. 2016; 16: 65.

[86] Jafarzadeh A, Paknahad MH, Nemati M, et al. Dysregulated expression and functions of microRNA-330 in cancers: a potential therapeutic target. Biomed Pharmacother. 2022; 146: 112600.

[87] Fu R, Shao Q, Yang B, et al. MiR-520a-5p/PPP5C regulation pattern is identified as the key to gemcitabine resistance in pancreatic cancer. Front Oncol. 2022; 12: 903484.

[88] Liu Y, Jin A, Quan X, et al. p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability. Cancer Cell Int. 2023; 23: 301.

[89] Gnanamony M, Demirkhanyan L, Ge L, et al. Circular dumbbell miR-34a-3p and -5p suppresses pancreatic tumor cell-induced angiogenesis and activates macrophages. Oncol Lett. 2021; 21: 75.

[90] Wang K, Chen Z, Qiao X, Zheng J. LncRNA NORAD regulates the mechanism of the miR-532-3p/Nectin-4 axis in pancreatic cancer cell proliferation and angiogenesis. Toxicol Res (Camb). 2023; 12: 425-432.

[91] Zhang J, Li J, Xiong Y, Li R. Circ_0000284 upregulates RHPN2 to facilitate pancreatic cancer proliferation, metastasis, and angiogenesis through sponging miR-1179. J Biochem Mol Toxicol. 2023; 37: e23274.

[92] Feng N, Jiao Z, Zhang Y, Yang B. Hsa_circ_0050102 regulates the pancreatic cancer development via miR-218-5p/PPME1 axis. J Clin Lab Anal. 2022; 36: e24247.

[93] Lin L, Xiao L, Jin C, et al. Circ_0058058 drives the malignant phenotypes and immune evasion of pancreatic cancer by the microRNA-557-dependent regulation of PDL1. Pancreas. 2022; 51: 1444-1454.

[94] Chen K, Wang Q, Liu X, Wang F, Yang Y, Tian X. Hypoxic pancreatic cancer derived exosomal miR-30b-5p promotes tumor angiogenesis by inhibiting GJA1 expression. Int J Biol Sci. 2022; 18: 1220-1237.

[95] Guo Z, Wang X, Yang Y, et al. Hypoxic tumor-derived exosomal long noncoding RNA UCA1 promotes angiogenesis via miR-96-5p/AMOTL2 in pancreatic cancer. Mol Ther Nucleic Acids. 2020; 22: 179-195.

[96] Zhao Q, Zhu Z, Xiao W, et al. Hypoxia-induced circRNF13 promotes the progression and glycolysis of pancreatic cancer. Exp Mol Med. 2022; 54: 1940-1954.

[97] Zhang L, Wu H, Zhang Y, Xiao X, Chu F, Zhang L. Induction of lncRNA NORAD accounts for hypoxia-induced chemoresistance and vasculogenic mimicry in colorectal cancer by sponging the miR-495-3p/hypoxia-inducible factor-1alpha (HIF-1alpha). Bioengineered. 2022; 13: 950-962.

[98] Bao B, Ali S, Ahmad A, et al. Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One. 2012; 7: e50165.

[99] Chen C, Demirkhanyan L, Gondi CS. The multifaceted role of miR-21 in pancreatic cancers. Cells. 2024: 13.

[100] Lian M, Mortoglou M, Uysal-Onganer P. Impact of hypoxia-induced miR-210 on pancreatic cancer. Curr Issues Mol Biol. 2023; 45: 9778-9792.

[101] Huang X, Zuo J. Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response. Acta Biochim Biophys Sin (Shanghai). 2014; 46: 220-232.

[102] Jia H, Chen X, Zhang L, Chen M. Cancer associated fibroblasts in cancer development and therapy. J Hematol Oncol. 2025; 18: 36.

[103] Mizutani Y, Kobayashi H, Iida T, et al. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Res. 2019; 79: 5367-5381.

[104] Donahue TR, Nguyen AH, Moughan J, et al. Stromal microRNA-21 levels predict response to 5-fluorouracil in patients with pancreatic cancer. J Surg Oncol. 2014; 110: 952-959.

[105] Zhou B, Lei JH, Wang Q, et al. Cancer-associated fibroblast-secreted miR-421 promotes pancreatic cancer by regulating the SIRT3/H3K9Ac/HIF-1alpha axis. Kaohsiung J Med Sci. 2022; 38: 1080-1092.

[106] Deng K, Zou F, Xu J, Xu D, Luo Z. Cancer-associated fibroblasts promote stemness maintenance and gemcitabine resistance via HIF-1alpha/miR-21 axis under hypoxic conditions in pancreatic cancer. Mol Carcinog. 2024; 63: 524-537.

[107] Richards KE, Xiao W, Hill R. On behalf of the usc pancreas research, cancer-associated fibroblasts confer gemcitabine resistance to pancreatic cancer cells through PTEN-targeting miRNAs in exosomes. Cancers (Basel). 2022: 14.

[108] Guo Y, Li H, Sun C. Exosomal miR-125b-5p derived from cancer-associated fibroblasts promotes the growth, migration, and invasion of pancreatic cancer cells by decreasing adenomatous polyposis coli (APC) expression. J Gastrointest Oncol. 2023; 14: 1064-1076.

[109] Qi R, Bai Y, Li K, et al. Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs. Drug Resist Updat. 2023; 68: 100960.

[110] Fang Y, Zhou W, Rong Y, et al. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp Cell Res. 2019; 383: 111543.

[111] Kong F, Li L, Wang G, Deng X, Li Z, Kong X. VDR signaling inhibits cancer-associated-fibroblasts' release of exosomal miR-10a-5p and limits their supportive effects on pancreatic cancer cells. Gut. 2019; 68: 950-951.

[112] Zhang L, Chen Y, Dai Y, et al. Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p. Mol Biol Rep. 2024; 51: 995.

[113] Pang W, Su J, Wang Y, et al. Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. Cancer Sci. 2015; 106: 1362-1369.

[114] Zhou P, Ding X, Du X, Wang L, Zhang Y. Targeting reprogrammed cancer-associated fibroblasts with engineered mesenchymal stem cell extracellular vesicles for pancreatic cancer treatment. Biomater Res. 2024; 28: 0050.

[115] Hu C, Xia R, Zhang X, et al. circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis. Mol Cancer. 2022; 21: 24.

[116] Zheng S, Hu C, Lin H, et al. circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-kappaB signaling pathway. J Exp Clin Cancer Res. 2022; 41: 71.

[117] Wang H, Tian T, Zhang J. Tumor-associated macrophages (TAMs) in colorectal cancer (CRC): from mechanism to therapy and prognosis. Int J Mol Sci. 2021; 22.

[118] Liu J, Cao X. Glucose metabolism of TAMs in tumor chemoresistance and metastasis. Trends Cell Biol. 2023; 33: 967-978.

[119] Su MJ, Aldawsari H, Amiji M. Pancreatic cancer cell exosome-mediated macrophage reprogramming and the role of MicroRNAs 155 and 125b2 transfection using nanoparticle delivery systems. Sci Rep. 2016; 6: 30110.

[120] Parayath NN, Hong BV, Mackenzie GG, Amiji MM. Hyaluronic acid nanoparticle-encapsulated microRNA-125b repolarizes tumor-associated macrophages in pancreatic cancer. Nanomedicine (Lond). 2021; 16: 2291-2303.

[121] Xi Q, Zhang J, Yang G, et al. Restoration of miR-340 controls pancreatic cancer cell CD47 expression to promote macrophage phagocytosis and enhance antitumor immunity. J Immunother Cancer. 2020; 8.

[122] Yang T, Han Y, Chen J, Liang X, Sun L. MiR-506 promotes antitumor immune response in pancreatic cancer by reprogramming tumor-associated macrophages toward an M1 phenotype. Biomedicines. 2023; 11(11).

[123] Husain K, Villalobos-Ayala K, Laverde V, et al. Apigenin targets microRNA-155, enhances SHIP-1 expression, and augments anti-tumor responses in pancreatic cancer. Cancers (Basel). 2022; 14(15).

[124] Geng Y, Fan J, Chen L, et al. A notch-dependent inflammatory feedback circuit between macrophages and cancer cells regulates pancreatic cancer metastasis. Cancer Res. 2021; 81: 64-76.

[125] Wang Y, Ge WL, Wang SJ, et al. MiR-548t-5p regulates pancreatic ductal adenocarcinoma metastasis through an IL-33-dependent crosstalk between cancer cells and M2 macrophages. Cell Cycle. 2024; 23: 169-187.

[126] Ala M. Noncoding ribonucleic acids (RNAs) may improve response to immunotherapy in pancreatic cancer. ACS Pharmacol Transl Sci. 2024; 7: 2557-2572.

[127] Wang X, Luo G, Zhang K, et al. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kgamma to promote pancreatic cancer metastasis. Cancer Res. 2018; 78: 4586-4598.

[128] Wang S, Gao Y. Pancreatic cancer cell-derived microRNA-155-5p-containing extracellular vesicles promote immune evasion by triggering EHF-dependent activation of Akt/NF-kappaB signaling pathway. Int Immunopharmacol. 2021; 100: 107990.

[129] Wang T, Ye L, Zhou Y, et al. Pancreatic cancer-derived exosomal miR-510 promotes macrophage M2 polarization and facilitates cancer cell aggressive phenotypes. Hum Cell. 2024; 38: 17.

[130] Guo Y, Cui J, Liang X, Chen T, Lu C, Peng T. Pancreatic cancer stem cell-derived exosomal miR-210 mediates macrophage M2 polarization and promotes gemcitabine resistance by targeting FGFRL1. Int Immunopharmacol. 2024; 127: 111407.

[131] Zhang T, Yu H, Bai Y, et al. Extracellular vesicle-derived LINC00511 promotes glycolysis and mitochondrial oxidative phosphorylation of pancreatic cancer through macrophage polarization by microRNA-193a-3p-dependent regulation of plasminogen activator urokinase. Immunopharmacol Immunotoxicol. 2023; 45: 355-369.

[132] Lin J, Liu Y, Liu P, et al. SNHG17 alters anaerobic glycolysis by resetting phosphorylation modification of PGK1 to foster pro-tumor macrophage formation in pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res. 2023; 42: 339.

[133] Yin Z, Zhou Y, Ma T, et al. Down-regulated lncRNA SBF2-AS1 in M2 macrophage-derived exosomes elevates miR-122-5p to restrict XIAP, thereby limiting pancreatic cancer development. J Cell Mol Med. 2020; 24: 5028-5038.

[134] Chang J, Li H, Zhu Z, et al. microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3. Cell Biol Toxicol. 2022; 38: 577-590.

[135] Guo Y, Wu H, Xiong J, Gou S, Cui J, Peng T. miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer. Cell Biol Toxicol. 2023; 39: 1203-1214.

[136] Zhang K, Li YJ, Peng LJ, Gao HF, Liu LM, Chen H. M2 macrophage-derived exosomal miR-193b-3p promotes progression and glutamine uptake of pancreatic cancer by targeting TRIM62. Biol Direct. 2023; 18: 1.

[137] Wang C, Zeng Q, Gul ZM, et al. Circadian tumor infiltration and function of CD8(+) T cells dictate immunotherapy efficacy. Cell. 2024; 187: 2690-2702.

[138] Tan SN, Hao J, Ge J, et al. Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39. J Exp Med. 2025: 222.

[139] Wang C, Li X, Zhang L, et al. miR-194-5p down-regulates tumor cell PD-L1 expression and promotes anti-tumor immunity in pancreatic cancer. Int Immunopharmacol. 2021; 97: 107822.

[140] Lo YL, Li CY, Chou TF, et al. Exploring in vivo combinatorial chemo-immunotherapy: addressing p97 suppression and immune reinvigoration in pancreatic cancer with tumor microenvironment-responsive nanoformulation. Biomed Pharmacother. 2024; 175: 116660.

[141] Yao J, Gao R, Luo M, et al. Exosomal LINC00460/miR-503-5p/ANLN positive feedback loop aggravates pancreatic cancer progression through regulating T cell-mediated cytotoxicity and PD-1 checkpoint. Cancer Cell Int. 2022; 22: 390.

[142] Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L. Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol. 2014; 292: 65-69.

[143] Ding G, Zhou L, Qian Y, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget. 2015; 6: 29877-29888.

[144] Xi Q, Chen Y, Yang GZ, et al. miR-128 regulates tumor cell CD47 expression and promotes anti-tumor immunity in pancreatic cancer. Front Immunol. 2020; 11: 890.

[145] Wang Y, Petrikova E, Gross W, et al. Sulforaphane promotes dendritic cell stimulatory capacity through modulation of regulatory molecules, JAK/STAT3- and microRNA-signaling. Front Immunol. 2020; 11: 589818.

[146] Liu J, Ye L, Lin K, et al. miR-4299 inhibits tumor progression in pancreatic cancer through targeting ADAM17. Mol Cell Biochem. 2023; 478: 1727-1742.

[147] Ou Z, Lu Y, Xu D, Luo Z. Hypoxia mediates immune escape of pancreatic cancer cells by affecting miR-1275/AXIN2 in natural killer cells. Front Immunol. 2023; 14: 1271603.

[148] Di Pace AL, Pelosi A, Fiore PF, et al. MicroRNA analysis of natural killer cell-derived exosomes: the microRNA let-7b-5p is enriched in exosomes and participates in their anti-tumor effects against pancreatic cancer cells. Oncoimmunology. 2023; 12: 2221081.

[149] Basso D, Gnatta E, Padoan A, et al. PDAC-derived exosomes enrich the microenvironment in MDSCs in a SMAD4-dependent manner through a new calcium related axis. Oncotarget. 2017; 8: 84928-84944.

[150] Li R, Hu Y, Hou S. An exploration of oral-gut pathogens mediating immune escape of pancreatic cancer via miR-21/PTEN axis. Front Microbiol. 2022; 13: 928846.

[151] Gu J, Zhang J, Huang W, et al. Activating miRNA-mRNA network in gemcitabine-resistant pancreatic cancer cell associates with alteration of memory CD4(+) T cells. Ann Transl Med. 2020; 8: 279.

[152] Sigorski D, Gulczynski J, Sejda A, Rogowski W, Izycka-Swieszewska E. Investigation of neural microenvironment in prostate cancer in context of neural density, perineural invasion, and neuroendocrine profile of tumors. Front Oncol. 2021; 11: 710899.

[153] Hanahan D, Monje M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell. 2023; 41: 573-580.

[154] Cervantes-Villagrana RD, Albores-Garcia D, Cervantes-Villagrana AR, Garcia-Acevez SJ. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduct Target Ther. 2020; 5: 99.

[155] Peng T, Guo Y, Gan Z, et al. Nerve growth factor (NGF) encourages the neuroinvasive potential of pancreatic cancer cells by activating the warburg effect and promoting tumor derived exosomal miRNA-21 expression. Oxid Med Cell Longev. 2022; 2022: 8445093.

[156] Dai W, Wu X, Li J, et al. Hedgehog-Gli1-derived exosomal circ-0011536 mediates peripheral neural remodeling in pancreatic cancer by modulating the miR-451a/VGF axis. J Exp Clin Cancer Res. 2023; 42: 329.

[157] Cheng K, Pan J, Liu Q, et al. Exosomal lncRNA XIST promotes perineural invasion of pancreatic cancer cells via miR-211-5p/GDNF. Oncogene. 2024; 43: 1341-1352.

[158] Martinez-Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021; 21: 669-680.

[159] Dey P, Kimmelman AC, DePinho RA. Metabolic codependencies in the tumor microenvironment. Cancer Discov. 2021; 11: 1067-1081.

[160] Yang Y, Ishak Gabra MB, Hanse EA, et al. MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1. Nat Commun. 2019; 10: 809.

[161] Lin J, Wang X, Zhai S, et al. Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1. J Hematol Oncol. 2022; 15: 128.

[162] Zhang D, He Z, Shen Y, Wang J, Liu T, Jiang J. MiR-489-3p reduced pancreatic cancer proliferation and metastasis by targeting PKM2 and LDHA involving glycolysis. Front Oncol. 2021; 11: 651535.

[163] Wang Y, Zhang F, Wu D, Wang Q, Nie L, Yu J. A novel circ_0099999/miR-330-5p/FSCN1 ceRNA crosstalk in pancreatic cancer. Autoimmunity. 2021; 54: 471-482.

[164] Wang SJ, Li XD, Wu LP, Guo P, Feng LX, Li B. MicroRNA-202 suppresses glycolysis of pancreatic cancer by targeting hexokinase 2. J Cancer. 2021; 12: 1144-1153.

[165] Wei Y, Wang M, Liang M, et al. Tumor-suppressive miR-323a inhibits pancreatic cancer cell proliferation and glycolysis through targeting HK-2. Pathol Int. 2022; 72: 617-630.

[166] Yu T, Li G, Wang C, et al. MIR210HG regulates glycolysis, cell proliferation, and metastasis of pancreatic cancer cells through miR-125b-5p/HK2/PKM2 axis. RNA Biol. 2021; 18: 2513-2530.

[167] Li H, Shen H, Xie P, et al. Role of long intergenic non-protein coding RNA 00152 in pancreatic cancer glycolysis via the manipulation of the microRNA-185-5p/Kruppel-like factor 7 axis. J Cancer. 2021; 12: 6330-6343.

[168] Hu Y, Tang J, Xu F, et al. A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p. J Exp Clin Cancer Res. 2022; 41: 69.

[169] Chen Y, Liu Y, Tao Q, et al. circPUM1 activates the PI3K/AKT Signaling pathway by sponging to promote the proliferation, invasion and glycolysis of pancreatic cancer. Curr Pharm Biotechnol. 2022; 23: 1405-1414.

[170] Ma Y, He X, Di Y, et al. Circular RNA LIPH promotes pancreatic cancer glycolysis and progression through sponge miR-769-3p and interaction with GOLM1. Clin Transl Med. 2024; 14: e70003.

[171] Zhou B, Lei JH, Wang Q, et al. LINC00960 regulates cell proliferation and glycolysis in pancreatic cancer through the miR-326-3p/TUFT1/AKT-mTOR axis. Kaohsiung J Med Sci. 2022; 38: 1155-1167.

[172] Yan B, Cheng L, Jiang Z, et al. Resveratrol inhibits ROS-promoted activation and glycolysis of pancreatic stellate cells via suppression of miR-21. Oxid Med Cell Longev. 2018; 2018: 1346958.

[173] Rencuzogullari O, Yerlikaya PO, Gurkan AC, Arisan ED, Telci D. Palbociclib negatively regulates fatty acid synthesis due to upregulation of AMPKalpha and miR-33a levels to increase apoptosis in Panc-1 and MiaPaCa-2 cells. Biotechnol Appl Biochem. 2022; 69: 342-354.

[174] Liu A, Xu J. Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1alpha axis. Clin Transl Oncol. 2021; 23: 1905-1914.

[175] Wang J, Wang B, Ren H, Chen W. miR-9-5p inhibits pancreatic cancer cell proliferation, invasion and glutamine metabolism by targeting GOT1. Biochem Biophys Res Commun. 2019; 509: 241-248.

[176] Ren P, Wu NA, Fu S, Wang W, Li QI, Cheng Q. miR-122-5p restrains pancreatic cancer cell growth and causes apoptosis by negatively regulating ASCT2. Anticancer Res. 2023; 43: 4379-4388.

[177] Zhou X, Liu K, Cui J, et al. Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. J Exp Clin Cancer Res. 2021; 40: 124.

[178] Kara G, Calin GA, Ozpolat B. RNAi-based therapeutics and tumor targeted delivery in cancer. Adv Drug Deliv Rev. 2022; 182: 114113.

[179] Chen Y, Gao DY, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev. 2015; 81: 128-141.

[180] Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017; 16: 203-222.

[181] Raimondi G, Gea-Sorli S, Otero-Mateo M, Fillat C. Inhibition of miR-222 by oncolytic adenovirus-encoded miRNA sponges promotes viral oncolysis and elicits antitumor effects in pancreatic cancer models. Cancers (Basel). 2021: 13.

[182] Baertsch MA, Leber MF, Bossow S, et al. MicroRNA-mediated multi-tissue detargeting of oncolytic measles virus. Cancer Gene Ther. 2014; 21: 373-380.

[183] Xie Y, Hang Y, Wang Y, et al. Stromal modulation and treatment of metastatic pancreatic cancer with local intraperitoneal triple miRNA/siRNA nanotherapy. ACS Nano. 2020; 14: 255-271.

[184] Wang Y, Zhang M, Zhang L, Zhou M, Wang E. Nanoparticles loaded with circ_0086375 for suppressing the tumorigenesis of pancreatic cancer by targeting the miR-646/SLC4A4 axis. Clin Exp Metastasis. 2023; 40: 53-67.

[185] Ferino A, Miglietta G, Picco R, Vogel S, Wengel J, Xodo LE. MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells. RNA Biol. 2018; 15: 1273-1285.

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