The loss of RNA N-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-methyladenosine (mA) program and modulate tumor-infiltrating CD8 T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an mA 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 mA 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-mA 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 mA methyltransferase in TAMs promotes CD8 T cell dysfunction and tumor progression.