Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan‐To‐Phenylalanine Substitutants in EBV‐Positive Gastric Cancer

Abstract Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon‐γ (IFN‐γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine‐2,3‐dioxygenase (IDO)‐ kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan‐to‐phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV‐positive GC continuously secreted IFN‐γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV‐positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV‐positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti‐tumor immunotherapy.