Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells

• DOI: 10.1038/s41419-024-06503-1
• Publication Date: 2024-02-15T12:02:58Z
• Authors: Chenfeng Han; Minmin Ge; Pengfei Xing; Tian Xia; Cangang Zhang; Kaili Ma; Yifu Ma; Shicheng Li; Wenhui Li; Xiaowei Liu; Baojun Zhang; Liyuan Zhang; Lianjun Zhang
• Keywords: 0303 health sciences; 03 medical and health sciences; QH573-671; Cytology; Article

Abstract Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer may preferentially rely on certain amino acids for rapid growth and metastasis. the other sufficient nutrient availability uptake are necessary mounting an effective cell anti-tumor response in tumor microenvironment (TME). Here we demonstrate that outcompete cystine due high Slc7a11 expression. This competition induces T-cell exhaustion ferroptosis, characterized by diminished memory formation cytokine secretion, increased PD-1 TIM-3 expression, as well intracellular oxidative stress lipid-peroxide accumulation. Importantly, either deletion or intratumoral supplementation improves immunity. Mechanistically, deprivation disrupts glutathione synthesis, but promotes CD36 mediated lipid dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) synthesis prevents upregulation, thus boosting Our findings reveal metabolic checkpoint orchestrates survival differentiation, highlight Gclc a potential therapeutic target enhancing function.