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Updated: May 23, 2025
Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer
Xiaohua Yang1, Tianzhang Kou1,2, Hongmiao Wang1,2
1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
Abstract:
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.
Insights
Cancer cells exploit S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) to resist immunotherapy. Supplementing SAM boosts T cell function and suppresses tumor growth in colorectal cancer (CRC) models.
Area of Science:
- Immunology
- Metabolomics
- Oncology
Background:
- Tumor microenvironment metabolites influence cancer progression and immune response.
- The metabolic interplay between T cells and tumor cells in immunotherapy resistance is not fully understood.
Purpose of the Study:
- Investigate metabolic heterogeneity in colorectal cancer (CRC).
- Elucidate the role of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in immunotherapy resistance.
Main Methods:
- Untargeted metabolomics on CRC patient samples.
- In vitro functional assays on T cell activation and effector functions.
- In vivo studies with SAM supplementation in tumor-bearing mice.
Main Results:
- Microsatellite stable (MSS) CRC exhibits elevated SAM and SAH metabolism.
- SAM and SAH initially enhance CD8+ T cell activation but are depleted by cancer cells, impairing T cell survival.
- SAM supplementation in vivo increased T cell proliferation, reduced exhaustion, and suppressed tumor growth.
Conclusions:
- Metabolic crosstalk between T cells and CRC cells drives immunotherapy resistance.
- Targeting SAM and SAH metabolism presents a potential therapeutic strategy for MSS CRC.
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