Anti-tumour immunity controlled through mRNA m⁶A methylation and YTHDF1 in dendritic cells.

Abstract

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies^1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response^3,4. Here we show that durable neoantigen-specific immunity is regulated by mRNA N⁶-methyadenosine (m⁶A) methylation through the m⁶A-binding protein YTHDF1⁵. In contrast to wild-type mice, Ythdf1-deficient mice show an elevated antigen-specific CD8⁺ T cell antitumour response. Loss of YTHDF1 in classical dendritic cells enhanced the cross-presentation of tumour antigens and the cross-priming of CD8⁺ T cells in vivo. Mechanistically, transcripts encoding lysosomal proteases are marked by m⁶A and recognized by YTHDF1. Binding of YTHDF1 to these transcripts increases the translation of lysosomal cathepsins in dendritic cells, and inhibition of cathepsins markedly enhances cross-presentation of wild-type dendritic cells. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1^-/- mice, implicating YTHDF1 as a potential therapeutic target in anticancer immunotherapy.