An Insulin‐Exosome‐TNFAIP8 Axis Drives Stromal Fibrosis and Therapeutic Resistance in Pancreatic Cancer

Hyperinsulinemia, a hallmark of obesity and type 2 diabetes, is an emerging risk factor for pancreatic ductal adenocarcinoma (PDAC), yet its contribution to tumor progression and stromal remodeling remains unclear. Here, we identify an insulin-exosome-TNFAIP8-STAT1 signaling axis that is associated with fibroblast phenotypic remodeling and desmoplastic progression. Insulin activates PI3K/AKT-RAB3A signaling to enhance secretion of TNFAIP8-enriched exosomes from PDAC cells. Internalized TNFAIP8 recruits the E3 ligase TRIM21 to facilitate STAT1 ubiquitination and degradation, leading to the induction of myofibroblastic CAF-associated features, accompanied by enhanced extracellular matrix deposition and tumor growth. High TNFAIP8 expression in patient tumors correlates with fibrosis and poor prognosis. In orthotopic models, TNFAIP8 silencing or lipid nanoparticle-mediated shTNFAIP8 delivery reduced fibrosis, suppressed tumor progression, and enhanced gemcitabine efficacy without evident toxicity, suggesting the feasibility of a therapeutic approach. These findings uncover a mechanistic framework linking metabolic dysregulation to fibroinflammatory remodeling in PDAC, and nominate TNFAIP8 as a promising stromal-targeted therapeutic candidate.