Role of IDO1 and GCN2–mTOR Signaling in CD8⁺ T-Cell Dysfunction in Breast Cancer

Abstract

Breast cancer growth and development are determined by the interactions between malignant epithelial cells, immune cells, and metabolic processes in the tumor microenvironment. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of the essential amino acid tryptophan to kynurenine, which may suppress antitumor T cell responses. Accumulation of tryptophan breakdown products and decreased tryptophan levels are associated with enhanced IDO1 expression and activity, which can lead to alterations in immunological responses and metabolic reprogramming. In particular, tryptophan restriction can trigger the general control nonderepressible 2 (GCN2)-eukaryotic initiation factor 2α (eIF2α) stress-response pathway and suppress mechanistic target of rapamycin (mTOR)-dependent nutrient and anabolic signaling, whereas kynurenine and related metabolites can modulate several additional pathways, including aryl hydrocarbon receptor signaling. These downstream effects of tryptophan restriction are potentially important in CD8^⁺ T cells and can alter their metabolic fitness, proliferation, activation, and cytotoxic effector functions, leading to impaired antitumor immunity. Overall, IDO1-driven tryptophan metabolism and the associated immunometabolic alterations may contribute to tumor immune escape in the setting of breast cancer. Although this hypothesis has been proposed, additional studies are needed to validate the causal associations between IDO1 expression, tryptophan availability and kynurenine levels, GCN2/eIF2α and mTOR signaling, and CD8^⁺ T cell responses.