Heat Shock Proteins in Pancreatic Cancer: Pathogenic Mechanisms and Clinical Implications

Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis, or proteostasis, especially under stressful envi-ronmental conditions such as hyperthermia, hypoxia, or the presence of reactive oxygen species. In pancreatic cancer, the expression of many HSP isoforms is dysregulated, con-tributing to the activation of mechanisms that promote tumor development, including proliferation, invasion, angiogenesis, treatment resistance, and cancer cachexia syndrome. HSPs are significant diagnostic and prognostic biomarkers. Some of them, such as HSP27, HSP70, and HSP90, have been shown to correlate with treatment response and patient survival. Others, including HSPA2 and HSPB6, may indicate an increased risk of disease recurrence. These proteins also represent promising therapeutic targets. Preclinical and clinical studies suggest that inhibiting HSP activity and associated signaling pathways may inhibit tumor growth and increase treatment efficacy. These therapeutic effects include inducing apoptosis, autophagy, and ferroptosis, as well as sensitizing cancer cells to chemotherapy and immunotherapy. This article summarizes the current knowledge about the role of HSPs in pancreatic cancer biology, their significance as biomarkers, and their potential therapeutic applications in treating pancreatic ductal adenocarcinoma (PDAC). Most studies conducted so far have been preclinical, and due to the promising results, further clinical investigation is warranted.