No abstract

Emerging evidence revealed important roles of tumor neoantigens in generating spontaneous antitumor immune responses and predicting clinical responses to immunotherapies 1 , 2 . Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in many patients, due to failures in mounting a sufficient and lasting antitumor immune response 3 , 4 . Here, we show that durable neoantigen-specific immunity is regulated by messenger RNA (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 ( Ythdf1 −/− ) mice exhibit an elevated antigen-specific CD8 + T cell antitumor response. Loss of YTHDF1 in classical dendritic cells (cDCs) enhanced the cross-presentation of tumor antigen 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 elevates translation of lysosomal cathepsins in DCs, with the inhibition of cathepsins markedly enhancing cross-presentation of the wild-type DCs. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1 −/− mice, implicating YTHDF1 as a new potential therapeutic target in anticancer immunotherapy.