CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
癌症对维生素 B2 的竞争为 T 细胞铁死亡创造代谢检查点
英文原题：Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
查看英文原题
Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
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研究概要
我们的结果表明，肿瘤性VB2竞争建立了一个驱动T细胞铁死亡的代谢检查点，而增强VB2摄取可重新激活T细胞，从而改善癌症免疫治疗。
中文摘要
肿瘤与T细胞之间的代谢竞争驱动免疫逃逸，但相关转运蛋白和机制在很大程度上仍不明确。在此，我们建立了CareSLCs平台，并发现SLC52A3介导的维生素B2（VB2）摄取对T细胞抗肿瘤免疫不可或缺。在机制上，VB2缺乏会损害线粒体呼吸和谷胱甘肽再生，导致线粒体自噬、不稳定铁蓄积和脂质过氧化，从而触发T细胞铁死亡。出乎意料的是，肿瘤优先使用SLC52A2而非SLC52A3来清除VB2并竞争性胜过T细胞。在免疫功能正常的宿主中，敲除肿瘤SLC52A2可增强T细胞功能，而不明显影响肿瘤内在生长。在临床上，肿瘤SLC52A2高表达与T细胞功能障碍和较差生存相关，而膳食VB2摄入与癌症风险降低相关。因此，补充VB2或过表达SLC52A3可增强CAR-T 细胞的抗肿瘤疗效。我们的结果表明，肿瘤对VB2的竞争建立了一个驱动T细胞铁死亡的代谢检查点，而增强VB2摄取可重新激活T细胞以改善癌症免疫治疗。
展开英文摘要原文
Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive.
Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity.
Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells.
Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks.
Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy.
Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.
论文信息
- 作者
- Chen H、Li C、Ke Y、Wu Z、Ou Z、Huang N、Lin Z、Gao H
- 第一作者单位
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, Guangdong, China; Guangzhou National Laboratory, Guangzhou 510005, Guangdong, China.China
- 通讯作者单位
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510120, Guangdong, China; Guangzhou National Laboratory, Guangzhou 510005, Guangdong, China; Guangzhou Medical University, Guangzhou 511436, Guangdong, China. Electronic address: bian_yingjie@gzlab.ac.cn.China
- 期刊
- Cell2026 Oct 6
- 原文标识
- PubMed 42838046 · DOI 10.1016/j.cell.2026.09.020
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