Abstract
Epigenetic modifications, especially N(6)-methyladenosine (m(6)A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m(6)A 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 m(6)A modification-related patterns based on 23 m(6)A regulators. A comprehensive analysis was performed to explore TME infiltration in different m(6)A modification-related patterns. Principal component analysis was performed to obtain the m(6)Ascore and to quantify m(6)A modification-related patterns in different individuals. Three distinct m(6)A modification-related patterns were identified by 23 m(6)A regulators. The pathway enrichment analysis showed that m(6)Acluster-A was associated with immune activation; m(6)Acluster-B was associated with carcinogenic activation; m(6)Acluster-C was prominently related to substance metabolism. M(6)Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m(6)Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m(6)Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m(6)Ascore 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 m(6)A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.