Characterization of mA RNA Methylation Regulators Predicts Survival and Immunotherapy in Lung Adenocarcinoma.

N-methyladenosine (mA) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between mA modification and tumorigenesis and response to immunotherapy. However, the overall influence of mA regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the mA modification patterns of 936 lung adenocarcinoma samples based on 24 mA regulators. First, we described the features of genetic variation in these mA regulators. Many mA regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three mA modification patterns using a consensus clustering method. mA cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, mA cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. mA cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the mA cluster C group. Subsequently, we constructed an mA score model that qualified the mA modification level of individual samples by using principal component analysis algorithms. Patients with high mA score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the mA score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high mA score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that mA modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of mA modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our mA score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.