Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Mechanisms and Therapeutic Strategies

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with morbidity and mortality driven by late diagnosis, a dense desmoplastic stroma, and resistance to conventional therapies. Over sequential therapeutic eras, treatment has progressed from early cytotoxic agents to metabolism-directed strategies. A central feature of PDAC biology is extensive metabolic reprogramming, largely controlled by the Kirsten rat sarcoma viral oncogene homologue (KRAS) protein, which promotes aerobic glycolysis, glutamine utilization, and mitochondrial oxidative phosphorylation to sustain tumor growth under nutrient-limiting conditions. Accordingly, therapeutic efforts have increasingly focused on exploiting these metabolic dependencies, including inhibitors of glycolysis, glutaminase, and mitochondrial complex I, which have shown encouraging results in preclinical studies. Constitutively elevated autophagy–lysosomal flux provides PDAC cells with the capacity for nutrient recycling and supports immune evasion by promoting the neighbor of <i>BRCA1</i> gene 1 (NBR1) protein-dependent degradation of major histocompatibility complex class I (MHC-I). Although inhibition of autophagy with hydroxychloroquine and related lysosomal inhibitors has provided proof of concept, their limited specificity has motivated the development of more selective approaches, such as Unc-51-like autophagy activating kinase 1 (ULK1) inhibitors and selective autophagy receptor-directed strategies. Emerging combination regimens that integrate autophagy blockade with KRAS/extracellular signal-regulated kinase (ERK) pathway inhibition, metabolic stress, or immune checkpoint blockade may help overcome chemoresistance and enhance anti-tumor immunity. Together, these advances underscore the therapeutic promise of targeting metabolic plasticity and autophagy in PDAC and lay the groundwork for rational next-generation combination strategies.