N6-methyladenosine (m6A) modification can regulate a variety of biological processes. However, the implications of m6A modification in lung adenocarcinoma (LUAD) remain largely unknown. Here, we systematically evaluated the m6A modification features in more than 2400 LUAD samples by analyzing the multi-omics features of 23 m6A regulators. We depicted the genetic variation features of m6A regulators, and found mutations of FTO and YTHDF3 were linked to worse overall survival. Many m6A regulators were aberrantly expressed in tumors, among which FTO, IGF2BP3, YTHDF1 and RBM15 showed consistent alteration features across 11 independent cohorts. Besides, the regulator-pathway interaction network demonstrated that m6A modification was associated with various biological pathways, including immune-related pathways. The correlation between m6A regulators and tumor microenvironment was also assessed. We found that LRPPRC was negatively correlated with most tumor-infiltrating immune cells. On the other hand, we established a scoring tool named m6Sig, which was positively correlated with PD-L1 expression and could reflect both the tumor microenvironment characterization and prognosis of LUAD patients. Comparison of CNV between high and low m6Sig groups revealed differences on chromosome 7. Application of m6Sig on an anti-PD-L1 immunotherapy cohort confirmed that the high m6Sig group demonstrated therapeutic advantages and clinical benefits. Our study indicated that m6A modification is involved in many aspects of LUAD and contributes to tumor microenvironment formation. A better understanding of m6A modification will provide more insights into the molecular mechanisms of LUAD and facilitate developing more effective personalized treatment strategies. A web application was built along with this study (http://www.bioinfo-zs.com/luadexpress/).

PD-L1 immunotherapy; lung adenocarcinoma; m6A; prognosis; tumor microenvironment; web application