Neutrophil Extracellular Traps in Pancreatic Ductal Adenocarcinoma: A Vicious Cycle in the Tumor Microenvironment and Targeted Interventions

Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils and initially identified for their role in antimicrobial defense. In recent years, growing evidence has demonstrated that NETs contribute to the development and progression of various malignancies. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive digestive-system cancer characterized by strong invasiveness and poor prognosis. Notably, substantial infiltration of NETs is frequently observed within the PDAC tumor microenvironment (TME). Clinical evidence indicates that this phenomenon is closely associated with metastatic progression and reduced patient survival. This review systematically elaborates how the PDAC TME recruits and activates neutrophils and induces NET formation through multiple pathways, including extracellular matrix (ECM) signaling, cell-cell interactions, cytokine secretion, and epigenetic dysregulation. In addition, it examines the mechanisms through which NETs, functioning as a regulatory hub, facilitate PDAC progression by inducing angiogenesis, altering the stromal structure, driving tumor cell proliferation and invasion, and creating an immunosuppressive environment. Finally, we summarize the latest therapeutic strategies targeting NETs in PDAC and provide an outlook on future research directions in this field.