The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth.

Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q+ TAMs are regulated by an RNA N 6-methyladenosine (m6A) program and modulate tumor-infiltrating CD8+ T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m6A methyltransferase Mettl14 drives CD8+ T cell differentiation along a dysfunctional trajectory, impairing CD8+ T cells to eliminate tumors. Mettl14 -deficient C1q+ TAMs show a decreased m6A abundance on and a higher level of transcripts of Ebi3 , a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8+ T cells and overcomes immunosuppressive impact in mice. We show that the METTL14 -m6A levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an m6A methyltransferase in TAMs promotes CD8+ T cell dysfunction and tumor progression. [Display omitted] • m6A on mRNA directly controls the specification and function of the C1q+ TAM • Mettl14 depletion in C1q+ TAM promotes the growth of diverse solid tumors • Macrophage-derived Ebi3 transcript with decreased m6A level drives T cell dysfunction • Mettl14 level in human tumor stroma is inversely correlated with T cell dysfunction Dong et al. discover an mRNA m6A-mediated post-transcriptional regulatory mechanism in C1q+ tumor-associated macrophages. The loss of Mettl14 encoding an m6A "writer" in these macrophages promotes the accumulation of Ebi3 mRNA in an m6A-dependent manner, thereby leading to CD8+ T cell dysfunction and tumor growth. [ABSTRACT FROM AUTHOR]