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Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL
Cai-Yuan Wu1, Chun-Xiang Huang1, Xiang-Ming Lao2
1Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
Abstract:
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.
Insights
Glucose deprivation inhibits primary tumors but paradoxically fuels lung metastasis by depleting natural killer (NK) cells. TIGIT blockade offers a potential therapeutic strategy against this glucose metabolism-driven metastasis.
Area of Science:
- Oncology
- Immunology
- Metabolic Research
Background:
- Targeting cancer cell glucose metabolism is a key therapeutic strategy.
- Glucose deprivation is known to suppress primary tumor growth.
Purpose of the Study:
- To investigate the paradoxical effect of glucose deprivation on tumor metastasis.
- To elucidate the underlying mechanisms of glucose deprivation-induced metastasis.
- To identify potential therapeutic targets for preventing metastasis.
Main Methods:
- Utilized low-carbohydrate diets and impaired in situ metabolism models.
- Investigated endoplasmic reticulum (ER) stress, HMG-CoA reductase degradation protein 1 (HRD1), and TRAIL ubiquitination.
- Analyzed exosome formation via the endosomal sorting complex required for transport (ESCRT) complex.
- Assessed macrophage polarization and natural killer (NK) cell exhaustion.
- Evaluated the efficacy of TIGIT blockade in preclinical models.
- Correlated glucose metabolism with clinical postoperative recurrence data across 15 cancer types.
- Compared plasma exosomal TRAIL with traditional markers (AFP, tumor size) for metastasis prediction.
Main Results:
- Glucose deprivation suppresses primary tumor growth but promotes lung metastasis by depleting NK cells via lung macrophages.
- Mechanistically, glucose deprivation induces ER stress, activating HRD1 to ubiquitinate TRAIL, which is packaged into exosomes.
- Exosomal TRAIL polarizes macrophages, leading to NK cell exhaustion and a pre-metastatic niche.
- TIGIT blockade inhibited metastasis and enhanced anti-tumor effects.
- Low glucose metabolism correlated with higher 2-year postoperative recurrence in 15 cancer types.
- Plasma exosomal TRAIL is a superior predictor of early postoperative lung metastasis compared to AFP and tumor size.
Conclusions:
- Glucose metabolism targeting presents a paradox, promoting metastasis despite inhibiting primary tumor growth.
- Exosomal TRAIL, induced by glucose deprivation-mediated ER stress and HRD1 activation, drives NK cell exhaustion and metastasis.
- TIGIT blockade is a promising therapeutic strategy to counter glucose deprivation-induced metastasis.
- Plasma exosomal TRAIL serves as a potent biomarker for predicting early lung metastasis.
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