Pancreatic cancer-derived EVs enriched in macrophage inhibitory factor (MIF) were internalized by Kupffer cells (F4/80+) activating signaling pathways (e.g., TGF-β secretion) that reprogrammed hepatic stellate cells (HStCs) (α-SMA+desmin+) toward a myofibroblastic phenotype with increased FN production and deposition that creates a fibrotic environment. Here, FN1 is linked to familial pancreatic carcinoma.