N⁶-methyladenosine (m⁶A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m⁶A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m⁶A 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 m⁶A modification patterns of 936 lung adenocarcinoma samples based on 24 m⁶A regulators. First, we described the features of genetic variation in these m⁶A regulators. Many m⁶A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m⁶A modification patterns using a consensus clustering method. m⁶A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m⁶A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m⁶A 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 m⁶A cluster C group. Subsequently, we constructed an m⁶A score model that qualified the m⁶A modification level of individual samples by using principal component analysis algorithms. Patients with high m⁶A 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 m⁶A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m⁶A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m⁶A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m⁶A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m⁶A 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.

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