Cancer cell · 22 authors, 13 centres
This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.
This preclinical study uses mouse models to show that ionizing radiation induces YTHDF2 in myeloid cells, which promotes immunosuppressive MDSCs and radioresistance; inhibiting YTHDF2 genetically or pharmacologically enhances radiotherapy and immunotherapy efficacy.
This preclinical study investigates the role of the m6A reader YTHDF2 in radiotherapy resistance. Using murine MC38 colon tumors and myeloid-specific Ythdf2 knockout mice, the authors demonstrate that ionizing radiation (IR) induces YTHDF2 expression via NF-κB signaling, which in turn promotes the expansion and immunosuppressive function of myeloid-derived suppressor cells (MDSCs). Genetic deletion of Ythdf2 in myeloid cells or pharmacological inhibition with a small molecule (DC-Y13-27) attenuates MDSC infiltration and suppressive function, thereby enhancing antitumor immunity and improving the efficacy of radiotherapy and anti-PD-L1 immunotherapy. Single-cell RNA sequencing revealed that YTHDF2 deficiency alters MDSC differentiation landscapes after IR. The study delineates an IR-YTHDF2-NF-κB circuit as a mechanism of extrinsic radioresistance. Limitations include the reliance on murine models, the potential for off-target effects of the tool inhibitor, small human sample sizes for validation, and the need for further mechanistic studies on specific immune cell subpopulations. The findings suggest YTHDF2 inhibition as a promising strategy to improve radio-immunotherapy outcomes.
