Methionine regulates the antitumor function of CD8+ T cells through polyamine synthesis
Date
2026
Authors
Zhao, Tian
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Abstract
As an essential amino acid, methionine (Met) is critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of Met on adoptive T cell therapies is unknown. Here, we examined the functionality of T cells under MR and methionine cycle inhibition (MAT2Ai) using in vitro models and a murine adoptive T cell therapy model. In vitro, transient MR or MAT2Ai increased interferon gamma (IFNγ) expression in CD8+ T cells, whereas prolonged MR or MAT2Ai led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and genetic ablation of a key gene in this pathway resembles the effect of MR on gamma (IFNγ) expression, indicating that transient MR enhanced T cell function by inhibiting polyamine synthesis. Despite this, pre-infusion transient MR of ovalbumin (OVA)-specific (OT-I) CD8+ T cells had no measurable impact on antitumor efficacy against EG7-OVA tumors in vivo. In contrast, an MR diet reduced intertumoral Met levels and promoted EG7-OVA tumor growth in mice treated with OT-I T cells, thereby confirming that Met is essential for the activity of adoptively transferred T cells. Collectively, these findings suggest that enhancing Met availability in the tumor microenvironment may improve the efficacy of adoptive T cell therapies.
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Keywords
T cell metabolism, Cancer immunology