Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by profound therapeutic resistance and a 5-year survival rate below 10%. This prognosis is largely driven by a highly immunosuppressive tumor microenvironment (TME), in which tumor-associated neutrophils (TANs) serve as pivotal regulators. Upon recruitment to the TME, neutrophils undergo functional polarization into distinct phenotypes that either antagonize or facilitate tumor progression. This review synthesizes recent advances in PDAC research, delineating the ontogeny, subpopulation heterogeneity, and molecular mechanisms governing the pro- or anti-tumorigenic effects of TANs. We emphasize the regulatory crosstalk between TANs and the immune microenvironment, highlighting key signaling axes such as TGF-β and C-X-C chemokine receptor 2 (CXCR2) pathways. Furthermore, we evaluate TAN-targeted therapeutic strategies, categorizing them into recruitment inhibition, functional reprogramming, and immunosuppression disruption. Finally, we discuss translational challenges, including biomarker development and the shift from neutrophil depletion to functional reprogramming, offering perspectives for overcoming therapeutic resistance in PDAC.