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

作者：Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng‐Jiang Zhu, Yuping Cai · 发表于：Cancer & Metabolism · 年份：2025 · DOI：10.1186/s40170-025-00394-2 · 被引用次数：5 · 研究领域：Cancer Research and Treatments、RNA modifications and cancer、Cancer, Hypoxia, and Metabolism

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.