{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T09:20:59Z","timestamp":1774430459685,"version":"3.50.1"},"reference-count":183,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"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 highly resistant to conventional immunotherapies due to its immunosuppressive tumor microenvironment. Interleukin-12 (IL-12), a potent immunostimulatory cytokine, has demonstrated remarkable therapeutic potential across a range of malignancies. However, systemic administration of IL-12 has been linked to severe dose-limiting toxicities, including cytokine release syndrome and multi-organ dysfunction, representing a persistent barrier to clinical translation. This review examines the rationale for IL-12-based immunotherapy in PDAC, synthesizing the current knowledge on immunotherapy approaches for this disease, IL-12\u2019s mechanisms of action in cancer treatment, and synergistic combination strategies. We describe three major delivery platforms that have emerged to overcome the limitations of systemic delivery due to toxicity: cellular encapsulation systems, virotherapy-mediated approaches, lipid nanocapsule formulations, polymer-based platforms, local electroporation-mediated transfection, and CAR-T combined therapy. These innovative strategies enable localized, sustained IL-12 expression within the tumor microenvironment while minimizing systemic exposure and associated toxicities. By safely harnessing IL-12\u2019s potent immunostimulatory properties, these next-generation delivery systems offer promising therapeutic avenues for PDAC and other immunotherapy-resistant malignancies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1755796","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:50:09Z","timestamp":1774421409000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting IL-12 for pancreatic cancer immunotherapy: advances in delivery strategies and clinical translation"],"prefix":"10.3389","volume":"17","author":[{"given":"Jessica","family":"Schlatter","sequence":"first","affiliation":[{"name":"Department of Visceral and Transplant Surgery, University Hospital Z\u00fcrich","place":["Z\u00fcrich, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of 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