YTHDF2 promotes tumor immune evasion by inhibiting CD8+ T cell-mediated anti-tumor immunity

Abstract YTHDF2 is a well-known m6A reader protein that binds and destabilizes m6A-modified mRNA. We have identified YTHDF2 as a novel regulator of antitumoral polarization in tumor-associated macrophages (TAMs). However, whether YTHDF2 regulates tumor immune evasion remains unknown. Here, we found that loss of YTHDF2 inhibited tumor growth and prolonged survival in syngeneic B16-OVA melanoma and MC38 colon cancer mouse models. Mechanistically, Ythdf2 deficiency-mediated immune remolding was multifactorial, involving promoting the recruitment and polarization of TAMs via chemoattractant CX3CL1, as well as impairing the tumor glycolysis metabolism and enhancing the mitochondrial respiration of tumor-infiltrating CD8+ T cells, thereby enhancing CD8+ T cell effector functions. We screened a small compound that can target YTHDF2 and promote its degradation. YTHDF2 degrader showed a potent anti-tumor effect and better efficacy when combined with anti-PD-L1 antibody therapy. Collectively, YTHDF2 is implicated as a regulator that orchestrates immune evasion and is a promising target to enhance cancer immunotherapy.