Emerging evidence highlights the potential of bioactive compounds, particularly polyphenols, as adjunctive therapeutic agents in the treatment of pancreatic cancer (PC), one of the most aggressive malignancies. This review focuses on epigallocatechin gallate (EGCG) and resveratrol due to their extensively documented anticancer activity, favorable safety profiles, and their unique ability to modulate multiple signaling pathways relevant to pancreatic tumorigenesis. Among polyphenols, these two have shown superior anti-cancer activity, epigenetic regulatory effects, and synergy with standard chemotherapies in preclinical pancreatic cancer models. Resveratrol exhibits anti-proliferative effects by modulating key signaling pathways, including phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt), nuclear factor kappa-B (NF-κB), and tumor protein 53 (p53). EGCG exerts anti-cancer activity by targeting multiple cellular processes, such as oxidative stress reduction, and suppression of inflammatory mediators like Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α). Both EGCG and resveratrol exert anti-pancreatic cancer effects partly through direct interactions with cell surface receptors and modulation of intracellular cascades. EGCG targets the 67 kDa laminin receptor (67LR), which is overexpressed in pancreatic cancer cells, triggering apoptosis, cyclic guanosine monophosphate (cGMP) production and activation of the PKCδ/acid sphingomyelinase (ASM) cascade. Resveratrol inhibits insulin-like growth factor-1 receptor (IGF-1R) activation of the PI3K/Akt and Wnt signaling pathways, while concurrently activating tumor suppressor p53. These interactions suppress proliferation, promote apoptosis, and reduce epithelial-mesenchymal transition (EMT), thereby limiting tumor progression. Both polyphenols enhance chemosensitivity and reduce resistance to conventional therapies, including gemcitabine, by modulating drug transporters and apoptotic pathways. Furthermore, their epigenetic influence, particularly via DNA methylation and histone modification, suggests a broader role in pancreatic cancer prevention. Understanding the roles and mechanisms of resveratrol and EGCG in pancreatic cancer provides valuable insights into novel treatment strategies. The integration of polyphenols into conventional therapeutic approaches may offer new hope for improving patient outcomes.
