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.

胰腺导管腺癌（PDAC）是一种实体恶性肿瘤，手术率极低，患者预后较差。因此，基于吉西他滨（GEM）的化疗仍然是 PDAC 最重要的治疗选择之一。然而，GEM单药治疗或GEM联合化疗在改善晚期PDAC患者生存方面的疗效非常有限，这主要是由于GEM耐药。 GEM耐药机制复杂且不清楚。肿瘤微环境（TME）中广泛而致密的纤维基质是PDAC的一个重要特征。越来越多的证据表明，这种纤维化 TME 不仅积极参与 PDAC 的生长和扩散，而且还有助于诱导 GEM 耐药性。代谢重塑减少了 PDAC 中的 GEM 运输和合成。本综述重点关注细胞外基质 (ECM)、免疫细胞和代谢重塑在诱导 GEM 抗性中的主要细胞和分子机制；强调将 TME 作为克服创业板阻力的重要战略的前景；并为化疗增敏和改善PDAC患者的整体预后提供新的精准干预措施。