Depletion of rRNA Methyltranferase METTL5 Enhances Anti-Tumor Immune Response via Neoantigen Generated from Cryptic Translation
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eLife Assessment
This study presents a valuable finding that depletion of the rRNA methyltransferase METTL5 enhances anti-tumor immunity through a novel mechanism involving neoantigen generation from non-canonical translation. The evidence supporting the central conclusions is solid, with comprehensive multi-omics data including ribosome profiling, immunopeptidomics, TCR sequencing, and multiple in vivo tumor models demonstrating synergy with immune checkpoint blockade.
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Abstract
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.
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eLife Assessment
This study presents a valuable finding that depletion of the rRNA methyltransferase METTL5 enhances anti-tumor immunity through a novel mechanism involving neoantigen generation from non-canonical translation. The evidence supporting the central conclusions is solid, with comprehensive multi-omics data including ribosome profiling, immunopeptidomics, TCR sequencing, and multiple in vivo tumor models demonstrating synergy with immune checkpoint blockade.
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Reviewer #1 (Public review):
Summary:
In this manuscript, Zhang et al. demonstrate that depletion of the 18S rRNA m6A methyltransferase Mettl5 compromises translation fidelity and consequently increases neoantigen generation, thereby uncovering an unexpected role for Mettl5 in tumor immunity. Mettl5-KO tumors exhibit enhanced CD8⁺ T-cell infiltration and show improved responses to immune checkpoint blockade. Mechanistically, loss of Mettl5 perturbs the local structure of 18S rRNA and disrupts the ribosome's ability to perform accurate translation. Subsequent ribosome profiling and mass spectrometry analyses provide compelling evidence that Mettl5 functions as a previously unrecognized regulator of translation to participate in tumor immune evasion.
Strengths:
This study presents a comprehensive set of experimental data supporting a …
Reviewer #1 (Public review):
Summary:
In this manuscript, Zhang et al. demonstrate that depletion of the 18S rRNA m6A methyltransferase Mettl5 compromises translation fidelity and consequently increases neoantigen generation, thereby uncovering an unexpected role for Mettl5 in tumor immunity. Mettl5-KO tumors exhibit enhanced CD8⁺ T-cell infiltration and show improved responses to immune checkpoint blockade. Mechanistically, loss of Mettl5 perturbs the local structure of 18S rRNA and disrupts the ribosome's ability to perform accurate translation. Subsequent ribosome profiling and mass spectrometry analyses provide compelling evidence that Mettl5 functions as a previously unrecognized regulator of translation to participate in tumor immune evasion.
Strengths:
This study presents a comprehensive set of experimental data supporting a mechanistic link between rRNA modification, translation fidelity, and neoantigen generation. The observed synergistic effect of Mettl5 depletion and anti-PD-1 therapy highlights the potential translational relevance of targeting rRNA modifications in cancer immunotherapy.
Weaknesses:
(1) In light of the principal function of Mettl5, which is to methylate 18S rRNA within the small ribosomal subunit, the authors focus primarily on translation fidelity, largely associated with elongation, but provide limited exploration of potential effects on translation initiation. Loss of Mettl5 may alter the initiation landscape, potentially promoting alternative or noncanonical initiation events (e.g., initiation at CUG codons), which could also contribute to the observed neoantigen repertoire changes. Further investigation into initiation-level alterations would strengthen the mechanistic interpretation.
(2) Given the broad involvement of rRNA methyltransferases in ribosome function, the authors should incorporate a parallel analysis using another enzyme (e.g., Zcchc4 or Nsun5) as a negative control. Such an experiment is essential to demonstrate that the tumor immunity phenotype observed is specific to Mettl5 rather than a general consequence of perturbing rRNA modification.
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Reviewer #2 (Public review):
Summary:
This study demonstrates that METTL5-mediated rRNA m⁶A1832 modification regulates tumor neoantigen generation by maintaining translational fidelity. Loss of METTL5 in tumor cells promotes immune cell infiltration into the tumor microenvironment and enhances the therapeutic efficacy of anti-PD-1 treatment, identifying a novel and potentially important target for cancer immunotherapy.
Strengths:
In murine tumor models, the authors found that Mettl5 depletion increases CD8⁺T cell infiltration and T cell receptor (TCR) repertoire diversity, and revealed a novel mechanism by which reduced ribosomal translation fidelity enhances non-canonical translation, thereby promoting the production of tumor neoantigens.
Weaknesses:
(1) While Mettl5 knockout enhances T-cell infiltration into tumors, it remains unclear …
Reviewer #2 (Public review):
Summary:
This study demonstrates that METTL5-mediated rRNA m⁶A1832 modification regulates tumor neoantigen generation by maintaining translational fidelity. Loss of METTL5 in tumor cells promotes immune cell infiltration into the tumor microenvironment and enhances the therapeutic efficacy of anti-PD-1 treatment, identifying a novel and potentially important target for cancer immunotherapy.
Strengths:
In murine tumor models, the authors found that Mettl5 depletion increases CD8⁺T cell infiltration and T cell receptor (TCR) repertoire diversity, and revealed a novel mechanism by which reduced ribosomal translation fidelity enhances non-canonical translation, thereby promoting the production of tumor neoantigens.
Weaknesses:
(1) While Mettl5 knockout enhances T-cell infiltration into tumors, it remains unclear whether loss of Mettl5 affects the expression of chemokines involved in immune cell recruitment.
(2) Although the authors report a significant reduction in tumor cell growth as well as tumor volume and weight, direct evidence demonstrating T-cell-mediated cytotoxicity is lacking.
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