Progress in the mechanistic understanding of NETs formation in cancer

Recent studies have revealed that the tumor microenvironment (TME) mediates neutrophil activation through multicomponent collaborative regulatory mechanisms, serving as a key driver of NETs formation. Cytokines, platelets, and complements activate neutrophil signaling pathways, ultimately forming NETs with protumorigenic properties in the TME. Notably, exogenous stimuli such as surgery, chronic stress, and pathogens can regulate NETs formation by remodeling the TME. However, the regulatory factors that induce NETs formation have not yet been systematically elucidated. Despite the identification of several factors that initiate the formation of NETs, the potential involvement of additional mechanisms remains inadequately understood. There is an urgent need for thorough mechanistic investigations utilizing cell lines and animal models in cancer. These studies will yield essential insights necessary for the formulation of targeted therapeutic approaches. This review delves into the mechanisms behind neutrophil extracellular traps (NETs) formation, tumor microenvironmental regulation of NETs formation, and exogenous stimuli that mediate tumor biological behaviors by inducing NETs. Gaining insight into these mechanisms will enhance our understanding of NETs and aid in crafting more precise strategies to inhibit tumor progression.