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.