Abstract 3287: TOX modulates methionine availability and enhances CD8+ T cell anti-tumor function in colorectal cancer

Abstract Colorectal cancers (CRC) with high TOX expression exhibit greater infiltration of CD8+ T cells, which display stronger tumor-killing capacity. This study investigates the metabolic mechanisms underlying the role of TOX in shaping the tumor microenvironment (TME) and its impact on CD8+ T cell function. Using LC-MS/MS metabolomics, we found that methionine and its metabolites are enriched in the TME of TOX-high CRC tumors. Further analysis revealed that TOX-high tumor cells express lower levels of the methionine transporter SLC43A2, reducing their methionine uptake. This methionine pool supports CD8+ T cell cytotoxicity and decreases apoptosis. In TOX-low tumors, we tested intratumoral methionine supplementation to assess its effect on tumor growth and CD8+ T cell activity. Supplementing methionine in TOX-low CRC tumors led to a significant reduction in tumor size and an increase in the proportion and activity of infiltrating CD8+ T cells. These results indicate that TOX modulates methionine metabolism by downregulating SLC43A2 in tumor cells, reducing competition with CD8+ T cells and enhancing their anti-tumor function. Our findings highlight TOX as a critical regulator of tumor metabolism and immune cell function, with potential as a therapeutic target for both immunotherapy and metabolic intervention strategies in CRC. Citation Format: Yujie Chang, Zhao Hui. TOX modulates methionine availability and enhances CD8+ T cell anti-tumor function in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3287.