Arginine Suppresses Tumorigenesis by Enhancing Antigen Presentation

Amino acids are often dysregulated in cancer, causing profound metabolic changes that support tumorigenesis. In a recent study, Wu and colleagues report that one such amino acid, arginine, can also suppress cancer progression by enhancing the translation of genes involved in immune surveillance. In analysis of publicly available datasets, arginine first emerged as one of the most commonly depleted amino acids in several disease contexts, including colon cancer. To better understand the implications of this, the authors conducted gene ontology analysis on proteomics data from both control and arginine-restricted human colon cancer cells (RKO). Strikingly, viral infection and antigen presentation were amongst the most highly enriched pathways, suggesting that arginine depletion may impact antitumor immune responses. Subsequent flow cytometry analyses revealed that the levels of arginine in RKO cell culture directly influenced surface expression of major histocompatibility complex (MHC) class I. These results extended to additional colon cancer cell lines, as well as representative cancer cell lines from other tissues (skin, breast, stomach, pancreas), suggesting a potentially universal arginine-dependent phenotype. In a chemically-induced colorectal carcinoma mouse model, animals fed an arginine-restricted diet exhibited larger, more frequent tumors than those receiving a normal control diet. Conversely, tumor burden was reduced in animals fed a high arginine diet. Tumorigenesis was unaffected by dietary arginine levels in animals lacking the MHC class I component β2-microglobulin, further indicating that arginine influences cancer progression through its regulation of the MHC-I complex. Functional cytotoxicity assays corroborated these findings, whereby engineered OVA peptide–presenting colon cancer cells were less efficiently killed when arginine was restricted prior to their coculture with CD8+ T cells. Upon excluding the possibility of transcriptional or metabolic regulation, further mechanistic studies revealed that arginine restriction disrupts the translation of MHC class I transcripts by codon-specific ribosome pausing, caused by arginine restriction–induced depletion of specific arginyl tRNAs. Supporting this model, synonymous codon substitution of affected MHC I transcripts, to alter tRNA usage, was sufficient to rescue antigen presentation and T-cell killing. Taken together, this study provides evidence that dietary and organismal arginine depletion supports cancer development by suppressing MHC class I translation, effectively enabling tumor immune evasion.Wu Q, Seydlitz LM, Iakimov V, Hsu DJ, Habibzadeh P, Hoffmann HH, et al. Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection. Cell 2026 Jul 30 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.