Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment

Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal gastrointestinal cancers, characterized by rapid progression and resistance to therapy driven by significant metabolic reprogramming. Although alterations in glycolysis, glutamine, and lipid metabolism are well established, recent studies emphasize a more crucial factor: the emergence of context-specific metabolic dependencies within the nutrient-deprived tumor microenvironment. This review highlights that focusing on these dependencies, particularly those resulting from the distinctive metabolic interactions between cancer cells and the surrounding stroma, offers a promising strategy for overcoming treatment challenges. Evidence demonstrating that stromal-driven metabolic pathways supply energy and building blocks and confer resistance to standard chemo- and immune-therapies is examined. Furthermore, innovative approaches to target these vulnerabilities in PDAC metabolic subtypes, including synthetic-lethal interactions and key transporters in metabolic pathways are explored. How functional precision medicine, which uses patient-derived models to identify metabolic vulnerabilities, may convert these insights into personalized therapies is examined. Moving from broad metabolic inhibition to precise targeting of the tumour-stroma metabolic ecosystem could substantially improve the prognosis for PDAC.