Zhao, Tian2026-01-282026-01-282026https://hdl.handle.net/1828/23081As 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.enAvailable to the World Wide WebT cell metabolismCancer immunologyThesisZhao, T., Carleton, G.A., Macpherson, S., Shiyuk, M., Monaghan, J., Han, J., Uchenunu, O., Rottapel, R., DeBerardinis, R.J., Stewart, K.M., et al. (2025). Methionine regulates antitumor function of CD8(+) T cells through polyamine synthesis. bioRxiv. 10.1101/2025.10.03.680201.Zhao, T., and Lum, J.J. (2022). Methionine cycle-dependent regulation of T cells in cancer immunity. Front Oncol 12, 969563. 10.3389/fonc.2022.969563.