Diverse RNA methylation patterns in neutrophils: key drivers in hepatocellular carcinoma

Neutrophils, crucial in the immune system, have recently been implicated in promoting malignancy. RNA methylation, an essential epigenetic feature, plays a key role in tumor microenvironment (TME) reprogramming. However, the relationship between neutrophils and RNA methylation in hepatocellular carcinoma (HCC) remains unclear.

We analyzed single-cell sequencing data from HCC, focusing on cell subtype and TME construction. RNA methylation "writers" were selected, and their expression in neutrophils was evaluated. Two neutrophil subtypes (high/low RNA methylation) were identified. Differentially expressed genes (DEGs) between these subtypes were confirmed, leading to the identification of 6 molecular subtypes via consensus clustering. A prognostic scoring system was developed using LASSO Cox regression, resulting in a novel neutrophil RNA methylation (NRM) scoring system to assess TME heterogeneity and clinical features.

TRPM3, specifically expressed in HCC-infiltrating neutrophils, may regulate RNA modification in tumor pathogenesis. HCC patients were stratified into low/high-NRM score groups, further refined into an advanced NRM (a-NRM) score by incorporating lncRNA data. High a-NRM scores correlated with advanced TNM stage, higher pathological grade, and increased suppressive immune cells. A nomogram incorporating the a-NRM score demonstrated a concordance index indicative of good predictive performance.

The a-NRM score is a reliable predictor of prognosis and could guide treatment selection in HCC patients, enhancing clinical response to immunotherapy. TRPM3 also presents as a potential therapeutic target in HCC.