YTHDF2 inhibition potentiates radiotherapy antitumor efficacy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• RNA N⁶-methyladenosine (m⁶A) modification plays a role in cancer progression.
• The influence of m⁶A on radiotherapy's antitumor effects and its mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of m⁶A, specifically YTHDF2, in the response to ionizing radiation (IR) and its impact on myeloid-derived suppressor cells (MDSCs).
• To explore YTHDF2 as a potential therapeutic target for enhancing radiotherapy and immunotherapy efficacy.

Main Methods:

• Utilized murine models and human samples to study the effects of IR on MDSC expansion and YTHDF2 expression.
• Investigated the impact of Ythdf2 deficiency in myeloid cells on antitumor immunity and tumor radioresistance.
• Analyzed the regulatory circuit involving IR, YTHDF2, and NF-κB signaling.

Main Results:

• Ionizing radiation (IR) induces expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs) and upregulates YTHDF2 expression.
• Loss of Ythdf2 in myeloid cells enhances antitumor immunity and overcomes tumor radioresistance by modulating MDSC differentiation, infiltration, and function.
• IR-induced YTHDF2 expression is dependent on NF-κB signaling, forming a positive feedback loop that enhances NF-κB activation.

Conclusions:

• YTHDF2 plays a critical role in mediating the immunosuppressive effects of radiotherapy by promoting MDSC expansion and function.
• Targeting YTHDF2 can reverse IR-induced immunosuppression and improve the efficacy of combined radiotherapy and anti-PD-L1 immunotherapy.
• YTHDF2 represents a promising therapeutic target for optimizing cancer treatment strategies involving radiotherapy and immunotherapy.