Disruption of tRNA threonylation triggers RIG-I mediated anti-tumour immune response
Tumour-induced mechanisms of immune evasion hinder immune response to cancer, particularly in melanoma. mRNA translation, by ensuring accurate protein synthesis, regulates cancer phenotypes and immune response, but the underlying mechanisms remain unclear. Here, we reveal how O-sialoglycoprotein endopeptidase (OSGEP), catalysing the tRNA modification N<sup>6</sup>-threonylcarbamoyladenosine (t<sup>6</sup>A), drives protein homeostasis in cancer cells to maintain T-cell exclusion and prevent anti-tumour immune response. t<sup>6</sup>A-deficient melanoma cells disrupt efficient cytoplasmic translation of ANN codons (trinucleotides with A in the first position and N = any nucleotide), causing specific protein aggregation and the formation of integrated stress response-dependent stress granules. We discovered that OSGEP loss triggers melanoma regression by relocating RIG-I to stress granules, leading to its pathway activation. As a result, T-cells are recruited to the tumour site and orchestrate an anti-tumour immune response. Finally, an OSGEP-driven gene signature in melanoma patients is associated with T-cell infiltration and improved overall survival. Together, our findings position t<sup>6</sup>A tRNA modification as a promising therapeutic target for melanoma treatment.
Authors
- Jochen Sven Utikal (ORCID: https://orcid.org/0000-0001-5316-0241)
- Lorena Martín-Morales (ORCID: https://orcid.org/0000-0002-1970-8872)
- Chloé Maurizy (ORCID: https://orcid.org/0000-0002-5176-7514)
- Timothy Budden (ORCID: https://orcid.org/0000-0003-2500-2814)
- Coralie Capron (ORCID: https://orcid.org/0000-0001-8922-3101)
- Christian Seca
- Elodie Renaude (ORCID: https://orcid.org/0000-0002-2269-2875)
- Cléa Dziagwa
- Miguel Ruiz
- Francesca Rapino (ORCID: https://orcid.org/0000-0002-4343-3805)
- Marine Leclercq (ORCID: https://orcid.org/0000-0002-3974-0060)
- Raphael Vanleyssem (ORCID: https://orcid.org/0009-0001-6838-7470)
- Amaya Virós (ORCID: https://orcid.org/0000-0001-5177-5015)
- Najla El Hachem (ORCID: https://orcid.org/0000-0002-4180-3016)
- Arnaud Blomme (ORCID: https://orcid.org/0000-0003-4183-8726)
- Pierre Close
- Alain Chariot
- Sylvain Delaunay
- Denis Heusdens
- Ning An
Institutions
- University of Liverpool (GB)
- University of Liège (BE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Salford Royal NHS Foundation Trust (GB)
- University of Manchester (GB)
- Cancer Research UK Manchester Institute (GB)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- DKFZ-ZMBH Alliance (DE)
- University Medical Centre Mannheim (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-25
- DOI
- https://doi.org/10.1038/s41467-026-69964-2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Melanoma Research Alliance
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Rosetrees Trust
- Fonds De La Recherche Scientifique - FNRS
- Fondation contre le Cancer
- Walloon excellence in life sciences and biotechnology
- Manchester Biomedical Research Centre