RNA N6-Methyladenosine Patterns in Hepatocellular Carcinoma Reveal a Distinct Immune Infiltration Landscape and Clinical Significance

BACKGROUND: RNA N6-methyladenosine (m(6)A) methylation, the most abundant and prominent form of epigenetic modification, is involved in hepatocellular carcinoma (HCC) initiation and progression. However, the role of m(6)A methylation in HCC tumor microenvironment (TME) formation is unexplored. This study aimed to reveal the TME features of HCC patients with distinct m(6)A expression patterns and establish a prognostic model based on m6A signatures for HCC cohorts. MATERIAL/METHODS: We classified the m(6)A methylation patterns in 365 HCC samples based on 21 m(6)A modulators using a consensus clustering algorithm. Single-sample gene set enrichment analysis algorithm was used to quantify the abundance of immune cell infiltration. Gene set variation analysis revealed the biological characteristics between the m6A modification patterns. The m(6)A-based prognostic model was constructed using a training set with least absolute shrinkage and selection operator regression and validated in internal and external datasets. RESULTS: Two distinct m(6)A modification patterns exhibiting different TME immune-infiltrating characteristics, heterogeneity, and prognostic variations were identified in the HCC cohort. After depicting the immune landscape of TME in HCC, we found patients with high LRPPRC m(6)A modulator expression had depletion of T cells, cytotoxic cells, dendritic cells, and cytolytic activity response. A high m(6)A score, characterized by suppression of immunity, indicated an immune-excluded TME phenotype, with poor survival. A nomogram was developed to facilitate HCC clinical decision making. CONCLUSIONS: Our results highlight the nonnegligible role of m(6)A methylation in TME formation and reveal a potential clinical application of the m(6)A-associated prognostic model for patients with HCC.