CRISPR research in pancreatic cancer is concentrated in four areas: building realistic disease models, identifying genetic dependencies, explaining metastasis and treatment resistance, and developing targeted therapies. Most work concerns pancreatic ductal adenocarcinoma (PDAC), where CRISPR can perturb genes such as KRAS, TP53, SMAD4, CDKN2A, STK11 and KDM6A in a controlled way. A 2025 review describes applications spanning signalling, proliferation, migration, invasion, chemotherapy resistance, tumour–immune interactions and genetically engineered models. (Lu, 2025)

Models of tumour initiation and progression. Researchers use CRISPR to introduce combinations of pancreatic-cancer mutations directly into adult mouse pancreata, avoiding lengthy breeding programmes. One platform created endogenous KrasG12D together with disruption of Trp53, Lkb1 or Arid1A, producing precursor lesions and PDAC. (Ideno, 2019) Multiplexed editing has also been used to induce pancreatic tumours, model deletions and translocations, and trace metastatic evolution. (Maresch, 2016) Human pancreatic organoids are another important application: CRISPR-mediated TP53 knockout produced organoids with increased proliferation, morphological transformation and increased expression of cancer-associated markers, providing a human-based system for studying early tumour biology and drug response. (Amare, 2025)

Functional genomics and biomarker discovery. Genome-scale knockout screens identify genes required for PDAC-cell survival and pathways that may be therapeutically exploitable. An early screen across eight pancreatic cancer cell lines identified recurrent essential genes and highlighted the SREBP metabolic pathway as a potential vulnerability, while also showing that apparent CRISPR dependencies can be affected by cell context and copy number. (Aguirre, 2016) In vivo screens extend this work into tumours: a screen of 125 recurrently mutated pancreatic-cancer genes identified USP15 and SCAF1 as tumour suppressors; loss of either increased sensitivity to PARP inhibition and gemcitabine. (Martinez, 2024) Other screens have linked PRKAR1A and STK11 loss to increased migration and liver metastasis, while HKDC1 loss reduced migration, illustrating how CRISPR can uncover metastasis regulators and candidate prognostic biomarkers. (Zhang, 2023) CRISPR screens are also being used to study immune resistance: in an immunocompetent PDAC model, loss of redox- and oxidative-stress genes sensitised tumours to CAR-T-cell therapy. (Froese, 2024)

Therapeutic strategies. The most developed target is mutant KRAS, particularly KRASG12D. In cell, orthotopic-tumour and patient-derived xenograft models, CRISPR-CasRx selectively silenced the mutant transcript, suppressed downstream signalling and tumour growth, improved gemcitabine sensitivity and increased mouse survival without obvious toxicity. (Jiang, 2020) Other work uses tumour-specific mutations that create new Cas9 PAM sites. Multiplexed guide RNAs then generate several DNA breaks in cancer cells while sparing matched normal cells; early studies reported selective killing in co-culture and strong tumour-growth inhibition in mouse xenografts. (Teh, 2025) A separate strategy disables NRF2 to remove chemotherapy resistance, with a conference abstract reporting lower chemotherapy requirements in experimental models; this remains an investigational approach rather than established treatment. (McGill, 2024) Delivery research includes AAV vectors, lipid nanoparticles and extracellular vesicles; a 2025 study reported exosome delivery of Cas9/sgRNA targeting KRASG12D in patient-derived PDAC cultures and an endoscopic injection model. (Gramatyuk, 2025)

The field is therefore promising but predominantly preclinical. A 2025 treatment review states that most pancreatic-cancer CRISPR studies remain at the cell- or animal-experiment stage, with unresolved problems involving delivery through the tumour microenvironment, tumour heterogeneity, off-target effects and long-term human safety. (Tian, 2025) The strongest near-term value of CRISPR is consequently as a research platform for causal gene testing, patient-derived modelling and treatment-resistance discovery; direct CRISPR treatment of pancreatic cancer still requires delivery, safety and clinical-validation studies.