The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response.

N6-Methyladenosine (m6A) is the most prevalent internal modification among mammalian mRNAs. Recent studies show that m6A methyltransferases, METTL3 and METTL14, play important roles in bladder carcinoma (BLCA). However, the impact of YTHDF2, a crucial m6A reader, has yet to be investigated. Here, we found that YTHDF2 is frequently up-regulated at both the RNA and protein level in bladder cancers. Functionally, YTHDF2 promotes the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively. Integrative RNA-sequencing and m6A-sequencing analyses show that RIG-I is a downstream target of YTHDF2. Mechanistically, YTHDF2 binds to the coding sequence of DDX58 mRNA and mediates its degradation in an m6A-dependent manner. Knock-down of RIG-I inhibits apoptosis and promotes the proliferation of BLCA cells. Depleting DDX58 also restores the phenotype abrogated by YTHDF2 deficiency. Moreover, bladder cancer Ythdf2-deficient cells implanted orthotopically activate an innate immune response and promote the recruitment of CD8+ T lymphocytes into the tumor bed and the urothelium. Consequently, targeting YTHDF2 may be beneficial in Bacillus Calmette-Guérin (BCG) immunotherapy. Our study reveals that YTHDF2 acts as an oncogene and RIG-I as a tumor suppressor in BLCA. These findings highlight the functional importance of the m6A modification in BLCA and implicate YTHDF2 as a potential therapeutic target of BLCA treatment.