Methionine Regulates Antitumour Function of CD8⁺ T Cells Through Polyamine Synthesis

Methionine is an essential amino acid 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 methionine on adoptive T cell therapies remains unknown. Here, we examined the functionality of T cells under MR and pharmaceutical inhibition of the methionine cycle (MAT2Ai), using primary T cells and a murine adoptive T cell therapy model. In vitro, transient MR or MAT2Ai treatment increased interferon gamma (IFNγ) expression in CD8⁺ T cells, whereas sustained MR led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and supplementation with polyamines reversed MR-induced IFNγ expression. Genetic ablation of S-adenosylmethionine decarboxylase, an enzyme involved in the polyamine synthesis pathway, recapitulated the effect of MR, indicating that transient MR enhances T cell function by inhibiting polyamine synthesis. Despite this, transient MR treatment of ovalbumin (OVA)-specific (OT-I) CD8⁺ T cells prior to adoptive transfer did not improve antitumour efficacy against EG7-OVA tumours in vivo. In contrast, sustained dietary MR accelerated EG7-OVA tumour growth in mice treated with OT-I T cells, demonstrating that methionine availability is essential for the activity of donor T cells. Importantly, sustained dietary MR promoted terminally exhausted phenotype in tumour-infiltrating donor CD8⁺ T cells, but not in host T cells. These findings suggest that enhancing methionine availability in the tumour microenvironment may improve the efficacy of adoptive T cell therapies.