Neutrophil extracellular traps-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in hepatocellular carcinoma

Background: Neutrophil extracellular traps (NETs) are released by neutrophils to capture invading pathogens. Recent studies show that NETs also play a significant role in tumorigenesis and cancer progression. However, the clinical significance of NET-related genes (NETRGs) in hepatocellular carcinoma (HCC) has not yet been fully elucidated.Methods: The transcriptomic and clinical data of HCC patients were extracted from The Cancer Genome Atlas, the International Cancer Genome Consortium, and Gene Expression Omnibus databases. The prognostic NETRGs were screened based on Kaplan-Meier and univariate COX analyses, and different molecular clusters corre-sponding to NETs-related modification patterns were identified by unsupervised clustering analyses. A NETs-related prognostic signature (NETRPS) was then constructed using least absolute shrinkage and selection oper-ator regression method, and the patients were accordingly classified into the low-risk and high-risk groups. The molecular clusters and risk groups were compared in terms of the tumor microenvironment characteristics, prognosis, therapeutic response and clinical characteristics through various bioinformatic methods.Results: Three distinct NETs-related clusters were identified, which were termed A, B and C. Notably, cluster C demonstrated high enrichment of infiltrating immune cells and stromal-related pathways, and was associated with worst prognosis. Furthermore, the low-risk group was characterized by better prognosis, stronger metabolic activation, higher immune cell infiltration, and greater responsiveness to immunotherapy, targeted and inter-ventional therapies compared to the high-risk group. The nomogram based on NETRPS and other clinical in-formation predicted patient prognosis with high accuracy.Conclusion: NETs play a significant role in shaping the biological and immune landscape of the HCC microen-vironment. NETRPS is a promising biomarker for predicting the prognosis and therapeutic responses of HCC patients.