t6A tRNA modification defines RIG-I mediated anti-tumour [Ribo-seq] immune response

The immune response in cancer, particularly in melanoma, is often hindered by tumour-induced immune evasion strategies, but the precise mechanisms for this remains unclear. Here, we reveal how the tRNA modification threonine-6-adenosine (t6A), mediated by O-sialoglycoprotein endopeptidase (OSGEP), maintains proteostasis in melanoma cells to prevent anti-tumour immune recognition. Cytoplasmic translation depends on the formation of t6A modification in position 37 of tRNANNU for efficient decoding of ANN codons. Defective protein homeostasis resulting from knockdown of OSGEP triggers accumulation of protein aggregates and the formation of stress granules. This disrupted codon-specific translation induces the activation of RIG-I and type I interferon response. Hence, t6A-deficient tumours prompt recruitment and activation of T-cells, affecting tumour growth. Finally, an OSGEP-driven gene signature in melanoma patients is predictive for T-cell infiltration and overall survival. Together, our results reveal t6A tRNA modification as a novel therapeutic target to fight melanoma.