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

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.