The Molecular Network of Neutrophil Extracellular Traps in Hepatocellular Carcinoma: Biogenesis, Function, and Therapeutic Implications

Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related death worldwide. Its high aggressiveness and resistance to therapy arise, in large part, from an immunosuppressive tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are web-like assemblies of chromatin and granular proteins released during NETosis, and they have emerged as major inflammatory drivers within the HCC TME. NETs actively promote tumor progression by physically trapping circulating tumor cells, remodeling the extracellular matrix, stimulating angiogenesis, and facilitating immune evasion. In this review, we systematically dissect the molecular networks that link NETs to HCC. We summarize the signaling pathways that regulate NETs formation, detail the multifaceted roles of NETs in hepatocarcinogenesis, metastasis, and therapy resistance, and assess the translational potential of NETs as diagnostic biomarkers and therapeutic targets. Together, these analyses offer theoretical guidance for developing the next generation of precision-medicine strategies for HCC.