Tumor microenvironment and metabolic remodeling in gemcitabine‐based chemoresistance of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a solid malignant tumor with a very low operative rate and a poor patient prognosis. Therefore, gemcitabine (GEM)-based chemotherapy remains one of the most important treatment choices for PDAC. However, the efficacy of GEM monotherapy or GEM combination chemotherapy in improving the survival of patients with advanced PDAC is very limited, primarily due to GEM resistance. The mechanism of GEM resistance is complex and unclear. An extensive and dense fibrous matrix in the tumor microenvironment (TME) is an important feature of PDAC. Increasing evidence indicates that this fibrotic TME not only actively participates in the growth and spread of PDAC but also contributes to the induction of GEM resistance. Metabolic remodeling reduces GEM transport and synthesis in PDAC. This review focuses on the main cellular and molecular mechanisms underlying the involvement of the extracellular matrix (ECM), immune cells, and metabolic remodeling in the induction of GEM resistance; highlights the prospect of targeting the TME as an essential strategy to overcome GEM resistance; and provides new precise interventions for chemotherapy sensitization and improving the overall prognosis of patients with PDAC.