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

Abstract

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 N⁶-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.

Keywords: EBI3; METTL14; T cell dysfunction; m(6)A epi-transcriptome; tumor microenvironment; tumor-associated macrophage.