RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
肿瘤浸润性调节性 T 细胞中的乳酸-α-酮戊二酸代谢回路通过诱导 NK 细胞衰老加速肿瘤进展
英文原题：A lactate-α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells accelerates tumor progression by inducing NK cell senescence.
查看英文原题
A lactate-α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells accelerates tumor progression by inducing NK cell senescence.
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中文摘要
调节性T（T reg）细胞可预防自身免疫性疾病，但会限制抗肿瘤免疫。肿瘤浸润Treg（Ti T reg）细胞表现出可作为潜在抗肿瘤靶点的代谢特征。在此，我们发现Ti-T reg细胞上调谷氨酸脱氢酶1（GDH1），增加α-酮戊二酸（α-KG）水平。Ti-T reg细胞中GDH1升高会加速肿瘤进展。机制上，在富含乳酸的微环境中，GDH1乳酰化促进α-KG生成，为Ti-T reg细胞中ALKBH5介导的Wnt2表达提供燃料。增强的WNT2促进自然杀伤（NK）细胞衰老。在Ti-T reg细胞中抑制GDH1或敲除SLC16A1可减少NK衰老并改善过继性NK转移治疗。我们揭示了一条驱动NK衰老的乳酸-α-KG代谢回路，为增强抗肿瘤免疫提供了治疗靶点。
展开英文摘要原文
Regulatory T (T reg ) cells prevent autoimmune diseases but limit antitumor immunity. Tumor infiltrating Treg (Ti T reg ) cells exhibit metabolic traits as potential antitumor targets.
Here, we find that Ti-T reg cells upregulate glutamate dehydrogenase 1 (GDH1), increasing -ketoglutarate ( -KG) levels. Elevated GDH1 in Ti-T reg cells accelerates tumor progression.
Mechanistically, in a lactate rich microenvironment, GDH1 lactylation boosts -KG production to fuel ALKBH5-mediated Wnt2 expression in Ti-T reg cells. Enhanced WNT2 promotes natural killer (NK) cell senescence. GDH1 inhibition or SLC16A1 deletion in Ti-T reg cells reduces NK senescence and improves adoptive NK transfer therapy.
We reveal a lactate- KG metabolic circuit driving NK senescence, offering therapeutic targets to boost antitumor immunity.
论文信息
- 作者
- Shi T、Ding Y、Chen Y、Tan X、Qu F、Xu D、Liu X、Li Y
- 第一作者单位
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China.China
- 通讯作者单位
- Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China. wangxiongjun@gzhu.edu.cn.China
- 期刊
- Nature cancer2026 Aug 18
- 原文标识
- PubMed 42613377 · DOI 10.1038/s43018-026-01210-6