Radiation induced YTHDF2 in dendritic cells impairs antitumor immunity

We reveal that ionized radiation (IR) induces the expression of m6A reader YTHDF2 in DCs with clinical significance, and the depletion of Ythdf2 in DCs augments the anti-tumor effect of RT. We observed that following IR, SPI-1 promotes the transcription of YTHDF2 in DCs. The IR-induced YTHDF2 in DCs directly targets and degrades m6A-binded Mfng, Aph-1b, and Aph-1c, which are essential for notch activation. YTHDF2 blockades in DCs activates notch signaling to promote the expression of MHC-I family gene Gm8909, thus enhancing cross-priming of CD8+ T cells to afford amplified anti-tumor effect of RT. Pharmacological inhibition of YTHDF2 in DC vaccines contributes to RT efficacy in both local tumor control and distant metastasis suppression. Our findings identify IR-induced YTHDF2 as an immunosuppressor in DCs, reveal the mechanism for regulating anti-tumor immunity, and open a new path for the development of m6A-mRNA targeting therapies. mRNA seq, RIPseq, and m6A-RIP seq profiling of YTHDF2 in tumor-infiltrating or tumor cell-coculturing dendritic cells from with or without treatment of irradiation