| First Author | Wang L | Year | 2023 |
| Journal | Cancer Cell | Volume | 41 |
| Issue | 7 | Pages | 1294-1308.e8 |
| PubMed ID | 37236197 | Mgi Jnum | J:337755 |
| Mgi Id | MGI:7506144 | Doi | 10.1016/j.ccell.2023.04.019 |
| Citation | Wang L, et al. (2023) YTHDF2 inhibition potentiates radiotherapy antitumor efficacy. Cancer Cell 41(7):1294-1308.e8 |
| abstractText | RNA N(6)-methyladenosine (m(6)A) modification is implicated in cancer progression. However, the impact of m(6)A 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-kappaB signaling; YTHDF2 in turn leads to NF-kappaB activation by directly binding and degrading transcripts encoding negative regulators of NF-kappaB signaling, resulting in an IR-YTHDF2-NF-kappaB 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. |
