Multi-omics analysis of m⁶A modification-related patterns based on m⁶A regulators and tumor microenvironment...

Epigenetic modifications, especially N⁶-methyladenosine (m⁶A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m⁶A modification in the TME of lung adenocarcinoma (LUAD) remains unclear. A total of 2506 patients with LUAD were included in the analysis and divided into different groups according to distinct m⁶A modification-related patterns based on 23 m⁶A regulators. A comprehensive analysis was performed to explore TME infiltration in different m⁶A modification-related patterns. Principal component analysis was performed to obtain the m⁶Ascore and to quantify m⁶A modification-related patterns in different individuals. Three distinct m⁶A modification-related patterns were identified by 23 m⁶A regulators. The pathway enrichment analysis showed that m⁶Acluster-A was associated with immune activation; m⁶Acluster-B was associated with carcinogenic activation; m⁶Acluster-C was prominently related to substance metabolism. M⁶Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m⁶Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m⁶Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m⁶Ascore exhibited significantly improved clinical response to anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) immunotherapy. This study explored the regulatory mechanisms of TME infiltration in LUAD. The comprehensive analysis of m⁶A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.