2025-07-17 中山大学(SYSU)
<関連情報>
- https://www.sysu.edu.cn/sysuen/info/1012/57091.htm
- https://www.cell.com/cell/abstract/S0092-8674(25)00728-7
グルコース制限により、エクソソームTRAILを介した肺の転移前自然免疫ランドスケープが形成される Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL
Cai-Yuan Wu ∙ Chun-Xiang Huang ∙ Xiang-Ming Lao ∙ … ∙ Limin Zheng ∙ Yuan Wei ∙ Dong-Ming Kuang
Cell Published:July 15, 2025
DOI:https://doi.org/10.1016/j.cell.2025.06.027
Graphical abstract
Highlights
- Low-carbohydrate diets or impaired glucose metabolism foster lung metastasis
- Glucose deprivation establishes a lung macrophage-dominated pre-metastatic niche
- Exosomal TRAIL polarizes PVR+ macrophages to trigger NK cell exhaustion in lungs
- Plasma exosomal TRAIL accurately predicts early postoperative lung metastasis
Summary
Targeting glucose metabolism has emerged as a promising strategy for inhibiting tumor growth. However, we herein uncover an unexpected paradox: while glucose deprivation through a low-carbohydrate diet or impaired in situ metabolism suppresses primary tumor growth, it simultaneously promotes lung metastasis by depleting natural killer (NK) cells via lung macrophages. Mechanistically, glucose deprivation induces endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1) to catalyze K63-linked ubiquitination of TRAIL, which is then packaged into exosomes via the endosomal sorting complex required for transport (ESCRT) complex. These exosomal TRAIL molecules polarize PVR+ macrophages, triggering NK cell exhaustion and establishing a pre-metastatic niche. Notably, TIGIT blockade not only prevents metastasis induced by glucose deprivation but also enhances its anti-tumor effects. Clinically, low glucose metabolism correlates with higher 2-year postoperative recurrence across 15 cancer types. Furthermore, plasma exosomal TRAIL outperforms traditional markers, such as α-fetoprotein (AFP) and tumor size, in predicting early postoperative lung metastasis, revealing both the risks and therapeutic potential of targeting glucose metabolism.
