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.
Radiotherapy induces YTHDF2 in dendritic cells impairing cross-presentation and T cell function
https://orcid.org/0000-0001-8109-8879
https://orcid.org/0000-0001-8340-5190
https://orcid.org/0000-0002-4416-116X
https://orcid.org/0000-0001-5300-6594
https://orcid.org/0000-0002-3046-8072
https://orcid.org/0000-0002-7508-8006
https://orcid.org/0000-0002-7817-7709
https://orcid.org/0009-0005-5445-9313
https://orcid.org/0000-0003-3217-7444
https://orcid.org/0000-0002-9983-5723
https://orcid.org/0000-0001-8851-7108
https://orcid.org/0000-0003-3056-7991
https://orcid.org/0000-0001-5512-8595
https://orcid.org/0000-0002-5643-8939
Disclosures: J. Bugno reported support from NIH grants T32GM007019 and K12CA139160. S.P. Pitroda reported grants from NIH U54 ROBIN, Cancer Research Foundation, LUNGevity Foundation, American Lung Association, and Ludwig Cancer Research Foundation during the conduct of the study; other from PersonaDx outside the submitted work; and had a patent to University of Chicago patents pending. C. He reported other from AllyRNA during the conduct of the study, and is a scientific founder, a member of the scientific advisory board, an equity holder of Aferna Bio, Inc. and Ellis Bio, Inc., a scientific cofounder and equity holder of Accent Therapeutics, Inc., and a member of the scientific advisory board of Rona Therapeutics and Element Biosciences. H.L. Liang reported a patent to 63/398,665 pending. R.R. Weichselbaum reported a patent to metastasis signatures pending and a patent to cGAS-STING IR pending, and had stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals, Inc., Magi Therapeutics, OncoSenescence, Aqualung Therapeutics Corporation, Cyntegron, Fuse Oncology, and PersonaDx. He has served in a consulting or advisory role for Aettis, Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano Proteagen, NKGen Biotech, Shuttle Pharmaceuticals, Highlight Therapeutics, S.L., and Aqualung Therapeutics Corporation. No other disclosures were reported.
