YTHDF2 inhibition potentiates radiotherapy antitumor efficacy

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations. [Display omitted] •YTHDF2 elevation in myeloid cells post RT correlates with poor outcome in patients•YTHDF2 depletion or inhibition in myeloid cells augments antitumor immunity of IR•YTHDF2 depletion alters MDSC subpopulations in blood and tumors after IR treatment•The YTHDF2-NF-κB circuit regulates MDSC migration and suppressive function Wang et al. discover that loss of Ythdf2 in myeloid cells augments antitumor immunity of ionizing radiation (IR). The IR-YTHDF2-NF-κB circuit governs MDSC migration and suppressive function. YTHDF2 inhibition enhances efficacy of radiation and checkpoint inhibitor.