Hypoxia-driven crosstalk between glycolysis and autophagy in pancreatic ductal adenocarcinoma: mechanisms, therapeutic vulnerabilities, and translational challenges

Pancreatic ductal adenocarcinoma (PDAC) develops within a poorly perfused, hypoxic, and nutrient-restricted microenvironment. Rather than treating glycolysis and autophagy as separate survival programs, this review examines their bidirectional coupling under metabolic stress. We distinguish direct crosstalk—where perturbing glycolytic flux or autophagic flux changes the other process—from indirect associations caused by shared upstream signals. HIF-1α, AMPK–mTOR signaling, lactate accumulation, redox stress, mitophagy, and tumor–stroma metabolite exchange are considered as context-dependent connecting modules. We critically assess evidence level, conflicting observations, therapeutic liabilities, and biomarker-based patient selection. The available data support a rationale for selected combination strategies, but they do not yet establish a universal clinical benefit from co-targeting glycolysis and autophagy in PDAC.