Depletion of rRNA Methyltranferase METTL5 Enhances Anti-Tumor Immune Response via Neoantigen Generated from Cryptic Translation

Tumor neoantigens play a pivotal role in eliciting tumor-specific immune responses and holds the promise for personalized immunotherapy. However, previous studies mainly focused on the tumor-specific neoantigens derived from genomic mutation and aberrant RNA splicing, limiting the repertoire of targetable neoantigens. Here, we demonstrate that inhibition of rRNA methyltransferase METTL5 translationally increases neoantigen production and enhances anti-tumor immunity. Mechanistically, METTL5-mediated m6A modification at the decoding center of small ribosomal subunit maintains the proper function of ribosome during mRNA translation. METTL5-deficiency decreases translation fidelity and increases production of tumor cell-specific antigens derived from non-canonical translation. Furthermore, we found that Mettl5-depletion increased CD8⁺T cell infiltration density and T cell receptor (TCR) repertoire diversity in murine tumor models. Importantly, this immunostimulatory effect strictly depended on intact antigen presentation pathways, suggesting that Mettl5 knockout exerts its effects primarily through neoantigen generation. Together, this study uncovers the intrinsic mechanisms sustaining mRNA translation accuracy, elucidates a novel source of tumor neoantigen generation, and proposes a new strategy to enhance immunotherapy through targeting mRNA translation.