胱氨酸
CD36
细胞生物学
CD8型
细胞毒性T细胞
癌症研究
化学
生物
免疫系统
免疫学
半胱氨酸
生物化学
基因
体外
酶
作者
Chenfeng Han,Minmin Ge,Pengfei Xing,Tian Xia,Cangang Zhang,Kaili Ma,Yong Ma,Shicheng Li,Wenhui Li,Xiaowei Liu,Baojun Zhang,Zhang Liyuan,Lianjun Zhang
标识
DOI:10.1038/s41419-024-06503-1
摘要
Abstract Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.
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