YTHDF2 inhibition potentiates radiotherapy antitumor efficacy

Cancer Cell. 2023 Jul 10;41(7):1294-1308.e8. doi: 10.1016/j.ccell.2023.04.019. Epub 2023 May 25.

Abstract

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.

Keywords: MDSCs; NF-kB; Radiation; YTHDF2; m6A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Humans
  • Mice
  • Myeloid Cells / metabolism
  • NF-kappa B* / metabolism
  • Neoplasms* / genetics
  • Neoplasms* / radiotherapy
  • RNA-Binding Proteins / metabolism
  • Signal Transduction

Substances

  • NF-kappa B
  • RNA-Binding Proteins
  • YTHDF2 protein, human
  • Ythdc2 protein, mouse