{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:53:42Z","timestamp":1791982422610,"version":"4.4.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":88,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, characterized by late-stage diagnosis, profound chemoresistance, and a five-year survival rate that barely exceeds 12%. The fibrotic stromal barrier surrounding the tumor actively suppresses immune infiltration and blocks drug delivery, rendering conventional treatment options largely ineffective. CRISPR\u2013Cas9-mediated gene knockout represents a promising strategy to overcome this stromal barrier-associated therapeutic resistance by enabling precise disruption of genes that sustain desmoplastic signaling, stromal-immune crosstalk, and drug efflux pathways within the tumor microenvironment. In this context, CRISPR-Cas9-guided gene knockout has opened a new chapter in PDAC research by enabling precise, scalable analysis of the cancer genome. Functional screens using this technology have mapped critical oncogenic dependencies, identifying mutant KRAS, TP53, SMAD4, and CDKN2A as high-value targets, while simultaneously revealing synthetic lethal interactions that were previously inaccessible through pharmacological approaches. These discoveries are now being translated into therapeutic strategies aimed at silencing driver mutations, restoring chemosensitivity, and reprogramming the immunosuppressive tumor microenvironment. Delivery platforms, including lipid nanoparticles, viral vectors, and extracellular vesicles, are being refined to navigate the physical barriers unique to PDAC. Patient-derived organoids and xenograft models are providing the translational framework needed to evaluate these interventions under clinically relevant conditions. This review examines the molecular mechanisms of CRISPR-guided knockout, the genetic vulnerabilities it has uncovered in PDAC, the therapeutic strategies emerging from this work, and the delivery systems supporting clinical translation. The remaining barriers and the steps needed to bring this technology to patients are also discussed.<\/jats:p>","DOI":"10.1007\/s12672-026-05532-w","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T22:13:11Z","timestamp":1784412791000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR guided gene knockout in pancreatic ductal adenocarcinoma molecular mechanisms and therapeutic strategies"],"prefix":"10.1007","volume":"17","author":[{"given":"Muhammad Shahid","family":"Mehmood","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maida","family":"Noor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somal","family":"Meraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arbab","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umad","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4680-3945","authenticated-orcid":false,"given":"Mohammad Jalal","family":"Nazari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"5532_CR1","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1007\/s12672-025-03383-5","volume":"16","author":"H Noormohamadi","year":"2025","unstructured":"Noormohamadi H, Soleimani Samarkhazan H, Kargar M, et al. CRISPR\/Cas technologies in pancreatic cancer research and therapeutics: recent advances and future outlook. Discov Oncol. 2025;16:1530.","journal-title":"Discov Oncol"},{"key":"5532_CR2","doi-asserted-by":"publisher","first-page":"5706","DOI":"10.3390\/ijms20225706","volume":"20","author":"E Lentsch","year":"2019","unstructured":"Lentsch E, Li L, Pfeffer S, et al. CRISPR\/Cas9-Mediated Knock-Out of KrasG12D Mutated Pancreatic Cancer Cell Lines. Int J Mol Sci. 2019;20:5706.","journal-title":"Int J Mol Sci"},{"key":"5532_CR3","doi-asserted-by":"publisher","first-page":"e073995","DOI":"10.1136\/bmj-2022-073995","volume":"383","author":"M Del Chiaro","year":"2023","unstructured":"Del Chiaro M, Sugawara T, Karam SD, et al. Advances in the management of pancreatic cancer. BMJ. 2023;383:e073995.","journal-title":"BMJ"},{"key":"5532_CR4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3390\/cancers9050042","volume":"9","author":"J Cicenas","year":"2017","unstructured":"Cicenas J, Kvederaviciute K, Meskinyte I, KRAS, et al. TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers. 2017;9:42.","journal-title":"Cancers"},{"key":"5532_CR5","doi-asserted-by":"crossref","unstructured":"Himanshu, Bashir M, Lone M, et al. The potential of noncoding RNAs-siRNAs in cancer research and therapy: challenges and solutions. In: Ullah MF, Ahmad A, editors. Non-coding RNAs. Cham: Springer Nature Switzerland. pp. 123\u201368.","DOI":"10.1007\/978-3-032-06948-1_5"},{"key":"5532_CR6","doi-asserted-by":"publisher","first-page":"eaaw8412","DOI":"10.1126\/scitranslmed.aaw8412","volume":"11","author":"A Lin","year":"2019","unstructured":"Lin A, Giuliano CJ, Palladino A, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019;11:eaaw8412.","journal-title":"Sci Transl Med"},{"key":"5532_CR7","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","volume":"575","author":"N Vasan","year":"2019","unstructured":"Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299\u2013309.","journal-title":"Nature"},{"key":"5532_CR8","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.3390\/cancers16213684","volume":"16","author":"R Oktriani","year":"2024","unstructured":"Oktriani R, Pirona AC, Kalm\u00e1r L, et al. Genome-Wide CRISPR Screen Identifies Genes Involved in Metastasis of Pancreatic Ductal Adenocarcinoma. Cancers. 2024;16:3684.","journal-title":"Cancers"},{"key":"5532_CR9","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3389\/fcell.2019.00239","volume":"7","author":"H Yang","year":"2019","unstructured":"Yang H, Bailey P, Pilarsky C. CRISPR Cas9 in Pancreatic Cancer Research. Front Cell Dev Biol. 2019;7:239.","journal-title":"Front Cell Dev Biol"},{"key":"5532_CR10","doi-asserted-by":"publisher","first-page":"1258096","DOI":"10.1126\/science.1258096","volume":"346","author":"JA Doudna","year":"2014","unstructured":"Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346:1258096.","journal-title":"Science"},{"key":"5532_CR11","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s12943-021-01431-6","volume":"20","author":"H Zhang","year":"2021","unstructured":"Zhang H, Qin C, An C, et al. Application of the CRISPR\/Cas9-based gene editing technique in basic research, diagnosis, and therapy of cancer. Mol Cancer. 2021;20:126.","journal-title":"Mol Cancer"},{"key":"5532_CR12","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1038\/s41587-020-0561-9","volume":"38","author":"AV Anzalone","year":"2020","unstructured":"Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020;38:824\u201344.","journal-title":"Nat Biotechnol"},{"key":"5532_CR13","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s12943-023-01925-5","volume":"23","author":"M Chehelgerdi","year":"2024","unstructured":"Chehelgerdi M, Chehelgerdi M, Khorramian-Ghahfarokhi M, et al. Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy. Mol Cancer. 2024;23:9.","journal-title":"Mol Cancer"},{"key":"5532_CR14","unstructured":"DNA targeting specificity. of RNA-guided Cas9 nucleases | Nature Biotechnology. https:\/\/www.nature.com\/articles\/nbt.2647. Accessed 2 Feb 2026."},{"key":"5532_CR15","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.tcb.2015.07.009","volume":"26","author":"R Ceccaldi","year":"2016","unstructured":"Ceccaldi R, Rondinelli B, D\u2019Andrea AD. Repair Pathway Choices and Consequences at the Double-Strand Break. Trends Cell Biol. 2016;26:52\u201364.","journal-title":"Trends Cell Biol"},{"key":"5532_CR16","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1146\/annurev.biochem.052308.093131","volume":"79","author":"MR Lieber","year":"2010","unstructured":"Lieber MR. The Mechanism of Double-Strand DNA Break Repair by the Nonhomologous DNA End-Joining Pathway. Annu Rev Biochem. 2010;79:181\u2013211.","journal-title":"Annu Rev Biochem"},{"key":"5532_CR17","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.3390\/cells9071608","volume":"9","author":"M Naeem","year":"2020","unstructured":"Naeem M, Majeed S, Hoque MZ, et al. Latest Developed Strategies to Minimize the Off-Target Effects in CRISPR-Cas-Mediated Genome Editing. Cells. 2020;9:1608.","journal-title":"Cells"},{"key":"5532_CR18","doi-asserted-by":"publisher","first-page":"e12677","DOI":"10.7554\/eLife.12677","volume":"5","author":"MA Horlbeck","year":"2016","unstructured":"Horlbeck MA, Witkowsky LB, Guglielmi B, et al. Nucleosomes impede Cas9 access to DNA in vivo and in vitro. eLife. 2016;5:e12677.","journal-title":"eLife"},{"key":"5532_CR19","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s12943-022-01518-8","volume":"21","author":"S-W Wang","year":"2022","unstructured":"Wang S-W, Gao C, Zheng Y-M, et al. Current applications and future perspective of CRISPR\/Cas9 gene editing in cancer. Mol Cancer. 2022;21:57.","journal-title":"Mol Cancer"},{"key":"5532_CR20","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nature16526","volume":"529","author":"BP Kleinstiver","year":"2016","unstructured":"Kleinstiver BP, Pattanayak V, Prew MS, et al. High-fidelity CRISPR\u2013Cas9 nucleases with no detectable genome-wide off-target effects. Nature. 2016;529:490\u20135.","journal-title":"Nature"},{"key":"5532_CR21","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.cell.2012.01.058","volume":"149","author":"H Ying","year":"2012","unstructured":"Ying H, Kimmelman AC, Lyssiotis CA, et al. Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism. Cell. 2012;149:656\u201370.","journal-title":"Cell"},{"key":"5532_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/synbio3010001","volume":"3","author":"D Stefanoudakis","year":"2025","unstructured":"Stefanoudakis D. Integrating CRISPR technology with key genetic markers in pancreatic cancer: a new frontier in targeted therapies. SynBio. 2025;3:1.","journal-title":"SynBio"},{"key":"5532_CR23","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0300-9084(01)01356-6","volume":"84","author":"DP Guimaraes","year":"2002","unstructured":"Guimaraes DP, Hainaut P. TP53: a key gene in human cancer. Biochimie. 2002;84:83\u201393.","journal-title":"Biochimie"},{"key":"5532_CR24","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nm.4219","volume":"23","author":"Z Steinhart","year":"2017","unstructured":"Steinhart Z, Pavlovic Z, Chandrashekhar M, et al. Genome-wide CRISPR screens reveal a Wnt\u2013FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. Nat Med. 2017;23:60\u20138.","journal-title":"Nat Med"},{"key":"5532_CR25","doi-asserted-by":"publisher","first-page":"28068","DOI":"10.1073\/pnas.2009899117","volume":"117","author":"X Wei","year":"2020","unstructured":"Wei X, Yang J, Adair SJ, et al. Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells. Proc Natl Acad Sci. 2020;117:28068\u201379.","journal-title":"Proc Natl Acad Sci"},{"key":"5532_CR26","doi-asserted-by":"publisher","first-page":"4091","DOI":"10.3390\/ijms21114091","volume":"21","author":"S Ciernikova","year":"2020","unstructured":"Ciernikova S, Earl J, Garc\u00eda Bermejo ML, et al. Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance? Int J Mol Sci. 2020;21:4091.","journal-title":"Int J Mol Sci"},{"key":"5532_CR27","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1007\/s12672-025-02231-w","volume":"16","author":"HT Hashim","year":"2025","unstructured":"Hashim HT, Alhatemi AQM, Fatima T, et al. Efficacy of CRISPR-Cas9 gene editing for targeting KRAS mutations in pancreatic cancer: a systematic review. Discov Oncol. 2025;16:596.","journal-title":"Discov Oncol"},{"key":"5532_CR28","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1053\/j.gastro.2018.03.039","volume":"155","author":"Y Kimura","year":"2018","unstructured":"Kimura Y, Fukuda A, Ogawa S, et al. ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice. Gastroenterology. 2018;155:194\u2013e2092.","journal-title":"Gastroenterology"},{"key":"5532_CR29","doi-asserted-by":"publisher","first-page":"e2113465119","DOI":"10.1073\/pnas.2113465119","volume":"119","author":"JS Long","year":"2022","unstructured":"Long JS, Kania E, McEwan DG, et al. ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis. Proc Natl Acad Sci. 2022;119:e2113465119.","journal-title":"Proc Natl Acad Sci"},{"key":"5532_CR30","doi-asserted-by":"publisher","first-page":"11507","DOI":"10.7150\/thno.46642","volume":"10","author":"W Jiang","year":"2020","unstructured":"Jiang W, Li H, Liu X, et al. Precise and efficient silencing of mutant KrasG12D by CRISPR-CasRx controls pancreatic cancer progression. Theranostics. 2020;10:11507\u201319.","journal-title":"Theranostics"},{"key":"5532_CR31","doi-asserted-by":"publisher","first-page":"e202000875","DOI":"10.26508\/lsa.202000875","volume":"4","author":"KM McAndrews","year":"2021","unstructured":"McAndrews KM, Xiao F, Chronopoulos A, et al. Exosome-mediated delivery of CRISPR\/Cas9 for targeting of oncogenic KrasG12D in pancreatic cancer. Life Sci Alliance. 2021;4:e202000875.","journal-title":"Life Sci Alliance"},{"key":"5532_CR32","doi-asserted-by":"publisher","first-page":"5137","DOI":"10.7150\/thno.42325","volume":"10","author":"Q Gao","year":"2020","unstructured":"Gao Q, Ouyang W, Kang B, et al. Selective targeting of the oncogenic KRAS G12S mutant allele by CRISPR\/Cas9 induces efficient tumor regression. Theranostics. 2020;10:5137\u201353.","journal-title":"Theranostics"},{"key":"5532_CR33","doi-asserted-by":"publisher","first-page":"109578","DOI":"10.1016\/j.celrep.2021.109578","volume":"36","author":"D Siolas","year":"2021","unstructured":"Siolas D, Vucic E, Kurz E, et al. Gain-of-function p53R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy. Cell Rep. 2021;36:109578.","journal-title":"Cell Rep"},{"key":"5532_CR34","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1038\/s42003-022-03994-6","volume":"5","author":"A Bertrand-Chapel","year":"2022","unstructured":"Bertrand-Chapel A, Caligaris C, Fenouil T, et al. SMAD2\/3 mediate oncogenic effects of TGF-\u03b2 in the absence of SMAD4. Commun Biol. 2022;5:1068.","journal-title":"Commun Biol"},{"key":"5532_CR35","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.canlet.2021.01.015","volume":"503","author":"S Sagar","year":"2021","unstructured":"Sagar S, Leiphrakpam PD, Thomas D, et al. MUC4 enhances gemcitabine resistance and malignant behaviour in pancreatic cancer cells expressing cancer-associated short O-glycans. Cancer Lett. 2021;503:91\u2013102.","journal-title":"Cancer Lett"},{"key":"5532_CR36","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1038\/s44321-024-00060-y","volume":"16","author":"S Wang","year":"2024","unstructured":"Wang S, Xiong Y, Luo Y, et al. Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma. EMBO Mol Med. 2024;16:1115\u201342.","journal-title":"EMBO Mol Med"},{"key":"5532_CR37","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s13046-022-02443-w","volume":"41","author":"S Zeng","year":"2022","unstructured":"Zeng S, Lan B, Ren X, et al. CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer. J Exp Clin Cancer Res. 2022;41:241.","journal-title":"J Exp Clin Cancer Res"},{"key":"5532_CR38","doi-asserted-by":"publisher","first-page":"15912","DOI":"10.1038\/s41598-024-66244-1","volume":"14","author":"P Mondal","year":"2024","unstructured":"Mondal P, Alyateem G, Mitchell AV, et al. A whole-genome CRISPR screen identifies the spindle accessory checkpoint as a locus of nab-paclitaxel resistance in a pancreatic cancer cell line. Sci Rep. 2024;14:15912.","journal-title":"Sci Rep"},{"key":"5532_CR39","doi-asserted-by":"publisher","first-page":"e003809","DOI":"10.1136\/jitc-2021-003809","volume":"10","author":"R Wang","year":"2022","unstructured":"Wang R, Chen J, Wang W, et al. CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model. J Immunother Cancer. 2022;10:e003809.","journal-title":"J Immunother Cancer"},{"key":"5532_CR40","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-025-03616-z","author":"A Mulero-S\u00e1nchez","year":"2026","unstructured":"Mulero-S\u00e1nchez A, Bosma A, Visuvasam B, et al. CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer. J Exp Clin Cancer Res. 2026. https:\/\/doi.org\/10.1186\/s13046-025-03616-z.","journal-title":"J Exp Clin Cancer Res"},{"key":"5532_CR41","doi-asserted-by":"publisher","first-page":"15965","DOI":"10.1038\/ncomms15965","volume":"8","author":"DE Biancur","year":"2017","unstructured":"Biancur DE, Paulo JA, Ma\u0142achowska B, et al. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat Commun. 2017;8:15965.","journal-title":"Nat Commun"},{"key":"5532_CR42","doi-asserted-by":"publisher","first-page":"7998","DOI":"10.3390\/ijms26167998","volume":"26","author":"AI Karkempetzaki","year":"2025","unstructured":"Karkempetzaki AI, Schatton T, Barthel SR. Galectin-9: An Emerging Glyco-Immune Checkpoint Target for Cancer Therapy. Int J Mol Sci. 2025;26:7998.","journal-title":"Int J Mol Sci"},{"key":"5532_CR43","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1158\/0008-5472.CAN-22-0391","volume":"83","author":"CM Goodwin","year":"2023","unstructured":"Goodwin CM, Waters AM, Klomp JE, et al. Combination Therapies with CDK4\/6 Inhibitors to Treat KRAS- Mutant Pancreatic Cancer. Cancer Res. 2023;83:141\u201357.","journal-title":"Cancer Res"},{"key":"5532_CR44","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1007\/s12672-025-03383-5","volume":"16","author":"H Noormohamadi","year":"2025","unstructured":"Noormohamadi H, Soleimani Samarkhazan H, Kargar M, et al. CRISPR\/Cas technologies in pancreatic cancer research and therapeutics: recent advances and future outlook. Discov Oncol. 2025;16:1530.","journal-title":"Discov Oncol"},{"key":"5532_CR45","doi-asserted-by":"publisher","first-page":"18741","DOI":"10.1038\/s41598-023-45964-w","volume":"13","author":"A Witz","year":"2023","unstructured":"Witz A, Dardare J, Francois A, et al. CRISPR\/Cas9-mediated knock-in of BRCA1\/2 mutations restores response to olaparib in pancreatic cancer cell lines. Sci Rep. 2023;13:18741.","journal-title":"Sci Rep"},{"key":"5532_CR46","doi-asserted-by":"publisher","first-page":"e194395","DOI":"10.1172\/JCI194395","volume":"136","author":"Y Xu","year":"2026","unstructured":"Xu Y, Nipper MH, Dominguez AA, et al. NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress. J Clin Invest. 2026;136:e194395.","journal-title":"J Clin Invest"},{"key":"5532_CR47","doi-asserted-by":"publisher","first-page":"1510179","DOI":"10.3389\/fimmu.2025.1510179","volume":"16","author":"H Meng","year":"2025","unstructured":"Meng H, Nan M, Li Y, et al. PD-L1 knockout or ZG16 overexpression inhibits PDAC progression and modulates TAM polarization. Front Immunol. 2025;16:1510179.","journal-title":"Front Immunol"},{"key":"5532_CR48","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.3390\/v13071288","volume":"13","author":"W Dong","year":"2021","unstructured":"Dong W, Kantor B. Lentiviral Vectors for Delivery of Gene-Editing Systems Based on CRISPR\/Cas: Current State and Perspectives. Viruses. 2021;13:1288.","journal-title":"Viruses"},{"key":"5532_CR49","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1101\/gad.264861.115","volume":"29","author":"S-H Chiou","year":"2015","unstructured":"Chiou S-H, Winters IP, Wang J, et al. Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR\/Cas9-mediated somatic genome editing. Genes Dev. 2015;29:1576\u201385.","journal-title":"Genes Dev"},{"key":"5532_CR50","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.omtm.2017.09.006","volume":"8","author":"KA Quirin","year":"2018","unstructured":"Quirin KA, Kwon JJ, Alioufi A, et al. Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice. Mol Ther Methods Clin Dev. 2018;8:8\u201320.","journal-title":"Mol Ther Methods Clin Dev"},{"key":"5532_CR51","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1016\/j.apsb.2021.05.020","volume":"11","author":"M Behr","year":"2021","unstructured":"Behr M, Zhou J, Xu B, et al. In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges. Acta Pharm Sin B. 2021;11:2150\u201371.","journal-title":"Acta Pharm Sin B"},{"key":"5532_CR52","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s41392-023-01309-7","volume":"8","author":"T Li","year":"2023","unstructured":"Li T, Yang Y, Qi H, et al. CRISPR\/Cas9 therapeutics: progress and prospects. Signal Transduct Target Ther. 2023;8:36.","journal-title":"Signal Transduct Target Ther"},{"key":"5532_CR53","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.cell.2020.03.023","volume":"181","author":"D Wang","year":"2020","unstructured":"Wang D, Zhang F, Gao G. CRISPR-Based Therapeutic Genome Editing: Strategies and In Vivo Delivery by AAV Vectors. Cell. 2020;181:136\u201350.","journal-title":"Cell"},{"key":"5532_CR54","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.3390\/pharmaceutics16091197","volume":"16","author":"M Kim","year":"2024","unstructured":"Kim M, Hwang Y, Lim S, et al. Advances in Nanoparticles as Non-Viral Vectors for Efficient Delivery of CRISPR\/Cas9. Pharmaceutics. 2024;16:1197.","journal-title":"Pharmaceutics"},{"key":"5532_CR55","doi-asserted-by":"publisher","first-page":"4420","DOI":"10.3390\/ijms26094420","volume":"26","author":"A Seijas","year":"2025","unstructured":"Seijas A, Cora D, Novo M, et al. CRISPR\/Cas9 Delivery Systems to Enhance Gene Editing Efficiency. Int J Mol Sci. 2025;26:4420.","journal-title":"Int J Mol Sci"},{"key":"5532_CR56","doi-asserted-by":"publisher","first-page":"573","DOI":"10.3390\/ijms23010573","volume":"23","author":"K Balon","year":"2022","unstructured":"Balon K, Sheriff A, Jack\u00f3w J, et al. Targeting Cancer with CRISPR\/Cas9-Based Therapy. Int J Mol Sci. 2022;23:573.","journal-title":"Int J Mol Sci"},{"key":"5532_CR57","doi-asserted-by":"publisher","first-page":"7353","DOI":"10.3390\/ijms21197353","volume":"21","author":"K Shalaby","year":"2020","unstructured":"Shalaby K, Aouida M, El-Agnaf O. Tissue-Specific Delivery of CRISPR Therapeutics: Strategies and Mechanisms of Non-Viral Vectors. Int J Mol Sci. 2020;21:7353.","journal-title":"Int J Mol Sci"},{"key":"5532_CR58","doi-asserted-by":"publisher","first-page":"4275","DOI":"10.1038\/s41467-018-06676-2","volume":"9","author":"K Szlachta","year":"2018","unstructured":"Szlachta K, Kuscu C, Tufan T, et al. CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response. Nat Commun. 2018;9:4275.","journal-title":"Nat Commun"},{"key":"5532_CR59","doi-asserted-by":"publisher","first-page":"115642","DOI":"10.1016\/j.addr.2025.115642","volume":"224","author":"J Gout","year":"2025","unstructured":"Gout J, Ekizce M, Roger E, et al. Pancreatic organoids as cancer avatars for true personalized medicine. Adv Drug Deliv Rev. 2025;224:115642.","journal-title":"Adv Drug Deliv Rev"},{"key":"5532_CR60","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1038\/s41374-018-0171-z","volume":"99","author":"N Ideno","year":"2019","unstructured":"Ideno N, Yamaguchi H, Okumura T, et al. A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPR-Cas9-mediated somatic recombination. Lab Investig J Tech Methods Pathol. 2019;99:1233\u201344.","journal-title":"Lab Investig J Tech Methods Pathol"},{"key":"5532_CR61","doi-asserted-by":"publisher","first-page":"117750","DOI":"10.1016\/j.biopha.2024.117750","volume":"182","author":"E Gayibov","year":"2025","unstructured":"Gayibov E, Sychra T, Sp\u00e1lenkov\u00e1 A, et al. The use of patient-derived xenografts and patient-derived organoids in the search for new therapeutic regimens for pancreatic carcinoma. A review. Biomed Pharmacother Biomedecine Pharmacother. 2025;182:117750.","journal-title":"Biomed Pharmacother Biomedecine Pharmacother"},{"key":"5532_CR62","doi-asserted-by":"publisher","unstructured":"Ge Zhu X. Deciphering cancer metabolic dependencies in the tumor microenvironment. Stud Theses Diss. 2021. https:\/\/doi.org\/10.48496\/0s0s-3160.","DOI":"10.48496\/0s0s-3160"},{"key":"5532_CR63","doi-asserted-by":"crossref","unstructured":"Torborg SR, Grbovic-Huezo O, Singhal A, et al. Solid tumor growth depends on an intricate equilibrium of malignant cell states. 2023; 2023.12.30.573100.","DOI":"10.1101\/2023.12.30.573100"},{"key":"5532_CR64","doi-asserted-by":"publisher","first-page":"3850","DOI":"10.3390\/cancers17233850","volume":"17","author":"F Morceau","year":"2025","unstructured":"Morceau F, El-Khoury V, Lee K, et al. Pancreatic Cancer Organoids: Modeling Disease and Guiding Therapy. Cancers. 2025;17:3850.","journal-title":"Cancers"},{"key":"5532_CR65","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.semcancer.2025.07.004","volume":"114","author":"Y Lu","year":"2025","unstructured":"Lu Y, Stoof J, Tano\u00e9 YR, et al. CRISPR\/Cas9 genome engineering in PDAC: From preclinical studies to translation and clinical research. Semin Cancer Biol. 2025;114:242\u201355.","journal-title":"Semin Cancer Biol"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-026-05532-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-026-05532-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-026-05532-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:28:41Z","timestamp":1791980921000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-026-05532-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,18]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5532"],"URL":"https:\/\/doi.org\/10.1007\/s12672-026-05532-w","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,18]]},"assertion":[{"value":"20 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Availability of data is not applicable as this study involves publicly available data.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Consent for publication is not applicable as this study involves publicly available data.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1436"}}