Radiotherapy induces YTHDF2 in dendritic cells impairing cross-presentation and T cell function
Metastatic progression is a major cause of radiotherapy (RT) failure, yet the mechanisms linking RT to immune suppression and metastasis remain unclear. Here, we identify YTHDF2 as a radiation-induced immune checkpoint in dendritic cells (DCs). By analyzing patient biopsies from a clinical trial (NCT03223155), we discover that increased YTHDF2 expression in DCs after RT correlates with treatment failure after RT. Mechanistically, ionizing radiation induces SPI1, which drives transcription of Ythdf2 in DCs. Upregulated YTHDF2 promotes m6A-mediated degradation of Notch pathway regulators (Mfng, Aph1b, Aph1c), impairing MHC-I cross-presentation and CD8+ T cell activation, thereby facilitating tumor immune evasion and metastatic spread. Crucially, targeting YTHDF2 restores DC immunogenicity, enhances RT-induced tumor control, and improves DC-based cancer vaccines when combined with RT, providing a clinically actionable strategy to overcome RT resistance and metastasis.
Authors
- Xiaona Huang (ORCID: https://orcid.org/0000-0002-9983-5723)
- Chuangyu Wen (ORCID: https://orcid.org/0000-0002-4416-116X)
- Xianbin Yu (ORCID: https://orcid.org/0000-0002-7508-8006)
- András Piffkó (ORCID: https://orcid.org/0000-0001-5300-6594)
- Sean P. Pitroda (ORCID: https://orcid.org/0000-0003-3056-7991)
- Fei Ji (ORCID: https://orcid.org/0009-0007-2309-7254)
- Jason Bugno (ORCID: https://orcid.org/0000-0002-3046-8072)
- Ralph R. Weichselbaum (ORCID: https://orcid.org/0000-0002-5643-8939)
- Steven J. Chmura (ORCID: https://orcid.org/0000-0001-8851-7108)
- Pingluan Wang (ORCID: https://orcid.org/0000-0002-7817-7709)
- Jiaai Wang (ORCID: https://orcid.org/0000-0003-3217-7444)
- Chuan He (ORCID: https://orcid.org/0000-0003-4319-7424)
- Emile Naccasha (ORCID: https://orcid.org/0009-0005-5445-9313)
- Liangliang Wang (ORCID: https://orcid.org/0000-0001-8340-5190)
- Dapeng Chen (ORCID: https://orcid.org/0000-0001-8109-8879)
- Hua Liang (ORCID: https://orcid.org/0000-0001-5512-8595)
Institutions
- Howard Hughes Medical Institute (US)
- Universität Hamburg (DE)
- University of Chicago (US)
- Institute of Microelectronics (SG)
- University Medical Center Hamburg-Eppendorf (DE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1084/jem.20250641
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00