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.