S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer

Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8⁺ T cells. Instead, cancer cells outcompete CD8⁺ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8⁺ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.