Fatty acids metabolic reprogramming and tumor microenvironment in pancreatic cancer: targeting pathways

Pancreatic ductal adenocarcinoma (PDAC) represents a highly aggressive form of pancreatic cancer. It is distinguished by a profound metabolic plasticity that supports its survival in a hypoxic and nutrient deprived microenvironment. Among the metabolic pathways altered in PDAC, fatty acid metabolism including synthesis, uptake, storage and β-oxidation serves as a key metabolic process that supports tumor growth, progression, and therapeutic resistance. This review discusses emerging evidence on fatty acid metabolic reprogramming and its relevance to the development and progression of pancreatic ductal adenocarcinoma. Key dysregulated enzymes as well as critical metabolic regulators are highlighted. Also, we discuss how genetic alterations drive lipogenic and oxidative pathways to sustain proliferation, redox balance, and adaptation to metabolic stress. Additionally, this review integrates current evidence to illustrate how the tumor microenvironment influences enhancing lipid availability and promoting metabolic symbiosis. Finally, this review outlines current pharmacological approaches that interfere with fatty acid metabolism, emphasizing lipid metabolism as a promising potential intervention strategy to inhibit tumor growth and sensitize cancer cells to existing treatments.