Inflammation and Type 1 interferon signaling in pancreatic adenocarcinoma: Insights into inflammasome driven crosstalk and therapeutic advances

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies, characterized by a profoundly immunosuppressive and inflammatory tumor microenvironment (TME). Chronic pancreatic inflammation not only drives tumor initiation and progression but also underpins therapeutic resistance. Among the key mediators of this inflammatory network, the traditionally recognized for their roles in antiviral defense, type I interferon (IFN-I) signaling and activation of multiprotein complexes, known as inflammasomes, have emerged as pivotal regulators of immune dynamics within PDAC. Under chronic immune stimulation, dysregulation of these pathways paradoxically promotes a pro-tumorigenic inflammatory milieu, rather than controlling immune defense, leading eventually to tumor growth by fostering immune evasion, fibrosis, and resistance to cytotoxic therapies. In this mini review, we summarize recent advances elucidating the interplay between chronic inflammation, IFN-I signaling, and inflammasome activity in PDAC pathophysiology. We highlight how aberrant crosstalk between these pathways remodels the TME, with focus on immune-TME, to support tumor survival and progression. Finally, we discuss emerging therapeutic strategies aimed at disrupting this IFN-I–inflammasome axis to reinvigorate anti-tumor immunity and enhance treatment efficacy. By integrating current evidence, this review provides new insights into inflammation-driven immune dysregulation in PDAC and underscores the potential of targeting inflammatory signaling as a promising avenue for therapeutic intervention. Schematic illustration of the dysregulated crosstalk between chronic Inflammation, type I Interferon, and inflammasome Signaling that drives Immune suppression and tumor progression in PDAC.