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Radiotherapy induces YTHDF2 in dendritic cells impairing cross-presentation and T cell function

Dapeng Chen1,2, Liangliang Wang3, Chuangyu Wen1,2

  • 1Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA.

The Journal of Experimental Medicine
|November 6, 2025
PubMed

Insights

Radiotherapy failure and metastasis are linked to radiation-induced immune suppression in dendritic cells (DCs). Targeting YTHDF2 in DCs overcomes this, enhancing cancer treatment and vaccines.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Metastatic progression is a primary reason for radiotherapy failure.
  • Mechanisms linking radiotherapy to immune suppression and metastasis are not well understood.

Purpose of the Study:

  • To identify radiation-induced immune checkpoints in dendritic cells (DCs).
  • To investigate the role of YTHDF2 in radiotherapy resistance and metastasis.
  • To explore YTHDF2 targeting as a therapeutic strategy.

Main Methods:

  • Analysis of patient biopsies from a clinical trial (NCT03223155).
  • Investigated the molecular mechanisms of YTHDF2 regulation by ionizing radiation.
  • Assessed the impact of YTHDF2 on T cell activation and tumor control in preclinical models.

Main Results:

  • Increased YTHDF2 expression in DCs post-radiotherapy correlates with treatment failure.
  • Ionizing radiation induces SPI1, which upregulates YTHDF2 in DCs.
  • YTHDF2 promotes degradation of Notch pathway regulators, impairing T cell activation and promoting immune evasion.
  • Targeting YTHDF2 restored DC immunogenicity and enhanced radiotherapy efficacy.

Conclusions:

  • YTHDF2 acts as a radiation-induced immune checkpoint in DCs.
  • Targeting YTHDF2 is a promising strategy to overcome radiotherapy resistance and metastasis.
  • Combination therapy with YTHDF2 inhibition and radiotherapy may improve cancer treatment outcomes and DC-based vaccines.

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