2. Academic Validation
  3. YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production

YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production

  • J Clin Invest. 2024 Sep 26:e181612. doi: 10.1172/JCI181612.
Chuangyu Wen 1,  Liangliang Wang 2,  András Piffkó 1,  Dapeng Chen 1,  Xianbin Yu 3,  Katarzyna Zawieracz 4,  Jason Bugno 1,  Kaiting Yang 1,  Emile Z Naccasha 1,  Fei Ji 1,  Jiaai Wang 1,  Xiaona Huang 1,  Stephen Y Luo 5,  Lei Tan 6,  Bin Shen 6,  Cheng Luo 7,  Megan E McNerney 4,  Steven J Chmura 1,  Ainhoa Arina 1,  Sean P Pitroda 1,  Chuan He 3,  Hua Liang 1,  Ralph R Weichselbaum 1
Affiliations

Affiliations

  • 1 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, United States of America.
  • 2 Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 3 Department of Chemistry, University of Chicago, Chicago, United States of America.
  • 4 Department of Pathology, University of Chicago, Chicago, United States of America.
  • 5 Biomedical Engineering Program, Northwestern University, Evanston, United States of America.
  • 6 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.
  • 7 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
PMID: 39325547 DOI: 10.1172/JCI181612
Abstract

RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in Cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from Cancer patients, but not in Other immune cells tested. Elevated YTHDF1 expression of DCs was associated with poor outcomes in patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) via increasing the cross-priming capacity of DCs across multiple murine Cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through STING-IFN-I signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine, significantly improving the therapeutic effect of RT and radio-immunotherapy in a murine melanoma model. Our findings reveal a new layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.

Keywords

Cancer immunotherapy; Dendritic cells; Immunology; Oncology; Radiation therapy.

Figures
Products