Metabolic sensing in 3D models of pancreatic ductal adenocarcinoma: probing pH, oxygen, and lactate dynamics to decode chemoresistance

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies due to its late diagnosis, extensive desmoplasia, and strong chemoresistance. Recent advances in three-dimensional (3D) in vitro modelling have provided new insights into tumor-stroma interactions and metabolic adaptations that drive disease progression. This review summarizes the pathogenesis and tumor microenvironment (TME) hallmarks of PDAC, emphasizing the metabolic heterogeneity characterized by altered pH, oxygen, and lactate gradients. It discusses conventional and emerging therapeutic strategies, the molecular basis of drug resistance, and the role of the TME in treatment failure. Furthermore, it highlights the evolution of 3D experimental models as physiologically relevant tools to study PDAC biology and evaluate drug efficacy. Special attention is given to the integration of optical biosensors for non-invasive spatio-temporal monitoring of pH and metabolic fluctuations. These sensing technologies, coupled with advanced bioengineered models, are paving the way for precision oncology and patient-tailored strategies in pancreatic cancer.