Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has driven the development of systemic arginine-depleting strategies, which are clinically safe but offer limited clinical benefit. Here, we demonstrated that under arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation, characterized by ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference was caused by a selective decrease in tRNAArg(UCU) levels following arginine deprivation, linked to METTL1-mediated tRNA modification. Proteomics and immunopeptidomics analyses validated that arginine shortage induced aberrant protein production at the endogenous level. T cell receptor (TCR) T cells that specifically recognize these HLA-presented mistranslated peptides efficiently killed cancer cells after arginine deprivation. These results lay the foundation for improved cancer therapies by combining systemic arginine-depleting strategies with TCR-based targeting of non-classical neoantigens.
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