Abstract 5242: YTHDF2 is a radiotherapy checkpoint in dendritic cells

Abstract Dendritic cells (DCs) play a central role for initiating anti-tumor immunity of T cells in radiotherapy (RT), yet its generalized success to cancer RT has been hampered by insufficient antigen presentation and induction of suppressive regulators from tumor microenvironment. Here, 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 Citation Format: Dapeng Chen, Hua Liang, Ralph Weichselbaum. YTHDF2 is a radiotherapy checkpoint in dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5242.