Anti-tumour immunity controlled through mRNA m 6 A methylation and YTHDF1 in dendritic cells.

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 N ⁶ -methyadenosine (m ⁶ A) methylation through the m ⁶ A-binding protein YTHDF1 ⁵ . 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 m ⁶ A 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.