二甲双胍
结直肠癌
CD8型
T细胞
细胞毒性T细胞
癌症研究
免疫系统
癌细胞
内科学
癌症
医学
内分泌学
生物
化学
免疫学
生物化学
体外
胰岛素
作者
Xiaowen Huang,Tiantian Sun,Jilin Wang,Xialu Hong,Huimin Chen,Tingting Yan,C. Zhou,Danfeng Sun,Chen Yang,TaChung Yu,Wenyu Su,Wan Du,Hua Xiong
标识
DOI:10.1158/0008-5472.c.6742368
摘要
<div>Abstract<p>Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating anti-tumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer (CRC). Herein, using single-cell RNA sequencing, we showed that metformin remodels the immune landscape of CRC. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the CRC tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in CRC cells and increased in CD8+ T cells. Untreated CRC cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T cell function. Metformin in turn reduced tryptophan uptake by CRC cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in CRC cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating CRC.</p></div>
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