There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response3,4. 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.
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The data that support the findings of this study are available from the corresponding author upon reasonable request. RIP–seq, Ribo-seq and m6A-seq datasets have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE115106. A summary of sequencing experiments is provided in Supplementary Table 3. The differential translational efficiency results provided in Supplementary Table 4. Source Data for bar graphs and box-plots in the Figures and Extended Data Figures are provided in separate Excel files.
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This study was supported by the National Key Research and Development Program of China, Stem Cell and Translational Research (2018YFA0109700 to D.H.), Strategic Priority Research Program of the Chinese Academy of Science (XDA16010404 to D.H.), National Institute of Health (HG008935 and GM113194 to C.H.), Ludwig Center at the University of Chicago (to C.H. and R.R.W.), CAS Hundred Talent Program (to D.H.), National Natural Science Foundation of China (31870890 to M.M.X., 31741074 to D.H.), National Science Fund for Excellent Young Scholars (31622039 to B.S.), Science Foundation for Distinguished Young Scholars of Jiangsu Province (BK20160045 to B.S.) and Open Project of Key Laboratory of Genomic and Precision Medicine of the CAS. The Mass Spectrometry Facility of the University of Chicago is funded by National Science Foundation (CHE-1048528). C.H. is an investigator of the Howard Hughes Medical Institute. We thank J. Tauler for editing.
Nature thanks J. Hanna, J. Neefjes and the other anonymous reviewer(s) for their contribution to the peer review of this work.