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Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production

ABSTRACT: Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has propelled the development of systemic arginine depletion strategies, which are clinically safe but have limited clinical benefit. Here, we demonstrate that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference is caused by a selective decrease in tRNAArg(UCU) levels after arginine deprivation, linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein production at the endogenous level. We further demonstrate that such inducible neopeptides are immunogenic, laying the foundation for improved cancer therapy combining systemic arginine depletion strategies with T-cell receptor-based targeting of non-classical neoantigens.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309074 | GEO | 2026/04/28

REPOSITORIES: GEO

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Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production [Ribo-Seq]

Project description:Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has propelled the development of systemic arginine depletion strategies, which are clinically safe but have limited clinical benefit. Here, we demonstrate that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference is caused by a selective decrease in tRNAArg(UCU) levels after arginine deprivation, linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein production at the endogenous level. We further demonstrate that such inducible neopeptides are immunogenic, laying the foundation for improved cancer therapy combining systemic arginine depletion strategies with T-cell receptor-based targeting of non-classical neoantigens.

2026-04-28 | GSE309063 | GEO

Arginine deprivation of ASS1-deficient cancers drives mistranslation and shared neoepitope production

Project description:Arginine biosynthesis is frequently suppressed in human cancer due to loss of argininosuccinate synthetase 1 (ASS1) expression, rendering cancer cells reliant on extracellular arginine. This observation propelled the development of systemic arginine depletion strategies, which are clinically safe but showed limited efficacy. Here, we show that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon-preference is caused by a selective decrease of tRNAArg(UCU) levels after arginine deprivation, which is linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein and neoepitope production at the endogenous level.

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Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production

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Chromatin accessibility governs the differential response of cancer and T-cells to arginine starvation (Illumina HumanHT-12 V4.0 beadchip)

Project description:Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase but it is unclear how these cancers, but not T-cells, tolerate arginine depletion. Here, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPbeta binding to a previously uncharacterized enhancer within ASS1. T-cells cannot induce ASS1, despite the presence of active ATF4 and CEBPbeta, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation which disrupts ATF4/CEBPbeta binding and target gene transcription. We find that T-cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T-cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.

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