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 (m(6)A) program and modulate tumor-infiltrating CD8(+) T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m(6)A 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 m(6)A 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-m(6)A 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 m(6)A methyltransferase in TAMs promotes CD8(+) T cell dysfunction and tumor progression.

Automated summary

The study reveals that the m(6)A methyltransferase Mettl14 in TAMs plays a role in modulating the function of CD8(+) T cells by regulating C1q(+) TAMs, ultimately affecting tumor progression.