We demonstrate that inhibition of rRNA methyltransferase METTL5 increases neoantigen production and enhances anti-tumor immunity. Mechanistically, METTL5-mediated m6A modification located at the decoding center of small ribosomal subunit maintains the proper conformation of ribosome during mRNA translation. METTL5 depletion leads to abnormal ribosome function, decreased translation fidelity, increased production of tumor cell-specific antigens derived from non-canonical translation, and subsequently induces an anti-tumor immune response.