Spatiotemporal heterogeneity of neutrophil extracellular traps in hepatocellular carcinoma microenvironment and targeted therapy progress

Neutrophil extracellular traps (NETs) form a spatiotemporally heterogeneous defensive architecture within the tumor microenvironment (TME), representing a newly identified multi-dimensional biological barrier system. Particularly in hepatocellular carcinoma (HCC), this system drives the heterogeneous evolution of the TME through the integration of mechanical stress transduction (YAP/TAZ activation) and protease-mediated signaling network remodeling (reconfiguration of intercellular signaling via proteolytic enzymes like MMP9, e.g. the MMP9/TGF-β axis).

The NET-driven heterogeneous evolution of the HCC TME is characterized by region-specific epithelial-mesenchymal transition (EMT) progression, metabolic reprogramming of tumor cells, and the formation of immunosuppressive niches within the TME. These changes collectively reshape the TME’s biological properties, alter the energy landscape of tumor cells (a framework describing dynamic metabolic/functional states of tumor cells shaped by microenvironmental cues), and maintain their stem cell properties, ultimately contributing to therapeutic heterogeneity and cross-regional drug resistance. Existing targeted therapeutic strategies against NETs in HCC and their clinical translational potential are analyzed herein.

This review systematically synthesizes the spatiotemporal heterogeneity of NETs in the HCC microenvironment and their functional roles, providing new insights into HCC treatment.