A lactate–α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells accelerates tumor progression by inducing NK cell senescence

IF 28 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2026-08-18 DOI:10.1038/s43018-026-01210-6

Tiezhu Shi, Yufeng Ding, Ying Chen, Xiangyin Tan, Fangfang Qu, Dongwei Xu, Xinyu Liu, Yixue Li, Yan-fang Liu, Xiaolin Zhang, Guanzhen Yu, Jialiang Shao, Xiongjun Wang

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引用次数: 0

Abstract

Regulatory T (Treg) cells prevent autoimmune diseases but limit antitumor immunity. Tumor‑infiltrating Treg (Ti‑Treg) cells exhibit metabolic traits as potential antitumor targets. Here, we find that Ti-Treg cells upregulate glutamate dehydrogenase 1 (GDH1), increasing α-ketoglutarate (α-KG) levels. Elevated GDH1 in Ti-Treg cells accelerates tumor progression. Mechanistically, in a lactate rich microenvironment, GDH1 lactylation boosts α-KG production to fuel ALKBH5-mediated Wnt2 expression in Ti-Treg cells. Enhanced WNT2 promotes natural killer (NK) cell senescence. GDH1 inhibition or SLC16A1 deletion in Ti-Treg cells reduces NK senescence and improves adoptive NK transfer therapy. We reveal a lactate–α‑KG metabolic circuit driving NK senescence, offering therapeutic targets to boost antitumor immunity. Shi et al show that a lactate–α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells promotes WNT2-mediated senescence-like features in natural killer cells and disrupting this axis hinders tumor progression.

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肿瘤浸润调节性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。

调节性T （Treg）细胞预防自身免疫性疾病，但限制抗肿瘤免疫。肿瘤浸润Treg （Ti - Treg）细胞表现出作为潜在抗肿瘤靶点的代谢特性。在这里，我们发现Ti-Treg细胞上调谷氨酸脱氢酶1 (GDH1)，增加α-酮戊二酸（α-KG）水平。Ti-Treg细胞中GDH1升高加速肿瘤进展。从机制上讲，在富含乳酸的微环境中，GDH1的乳酸化促进α-KG的产生，从而促进Ti-Treg细胞中alkbh5介导的Wnt2表达。增强的WNT2促进自然杀伤细胞（NK）衰老。Ti-Treg细胞中GDH1抑制或SLC16A1缺失可减少NK衰老，改善过继NK转移治疗。我们揭示了乳酸-α - KG代谢回路驱动NK衰老，提供了增强抗肿瘤免疫的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.