Background: Pancreatic cancer, particularly adenocarcinoma, is the fourth leading cause of cancer deaths globally and predicted to become the second most common by 2030. NF-κB is activated in pancreatic cancer, affecting tumor-immune communication, cell proliferation, and migration, regulated by canonical and noncanonical pathways. Chronic inflammation increases proinflammatory cytokines like IL-6, which affect pancreatic cancer progression. IL-6 activates pathways like JAK-STAT3, MAPK, and androgen receptors, promoting pancreatic intraepithelial neoplasia. Myofibroblast-like pancreatic stellate cells secrete high levels of IL-6, which promotes cancer cell proliferation through Nrf2-mediated metabolic reprogramming. IL6/STAT3 inhibits this growth and progression, while SOCS3 downregulates the pathway. Toll-like receptors (TLRs) are involved in pancreatic cancer, triggered by inflammation and DAMPs. Enhanced TLR expression affects prognosis, survival, migration, and progression, with TLR7 or -8 expression linked to UICC stage. TGF-β signaling is crucial in pancreatic cancer, affecting 100% of cases. It suppresses tumors in early stages, promotes apoptosis, and plays a dual role in oncogenesis and tissue development.