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.

Highlights

1, A low-carbohydrate diet or impaired glucose metabolism promotes lung metastases

This study reveals the association between glucose metabolism and lung metastasis risk through clinical and animal model approaches. Analysis of TCGA cancer database and postoperative data from Sun Yat-sen University Cancer Center showed that patients with lower expression of key glycolytic enzymes (e.g., HK2, LDHA) in tumor tissues were more prone to lung metastasis and had poorer prognosis. In mouse models, systemic glucose restriction achieved through low-carbohydrate diet (LCD) or genetic knockout of glycolytic enzymes significantly inhibited primary tumor growth but promoted formation of distant lung metastases—a phenomenon consistent across multiple tumor models. These findings suggest that the traditional metabolic intervention strategy of "anti-cancer through glucose control" may paradoxically increase metastasis risks under specific conditions.

2, Glucose deficiency can establish a macrophage-dominated pretransmission niche in the lungs

Through further analysis of the pulmonary immune microenvironment, researchers discovered that glucose restriction reshapes innate immune cell composition, establishing a pre-metastatic niche dominated by macrophages. ScRNA-seq and flow cytometry analyses revealed a significant increase in lung macrophages (CD11b⁺F4/80⁺) with enhanced expression of factors like CD86, IL-1β, and CXCL1, indicating an immunomodulatory pro-inflammatory phenotype that may facilitate immune microenvironment remodeling. Although NK cell numbers remained stable, their expression of effector molecules such as IFN-γ and GZMB was markedly reduced, demonstrating functional depletion characteristics that provide immune escape opportunities for metastatic cells.

3, Tumor-derived exosomes TRAIL can polarize PVR⁺ macrophages and induce NK cell depletion in the lung

At the mechanistic level, studies have demonstrated that glucose restriction induces endoplasmic reticulum stress in tumor cells, activates E3 ubiquitin ligase HRD1, and promotes TRAIL protein-specific loading into exosomes via K63 ubiquitination. These TRAIL-rich exosomes are preferentially taken up by pulmonary macrophages, which subsequently activate the NF-κB signaling pathway to induce high surface expression of immune checkpoint ligand PVR (CD155). Binding of PVR to NK cell surface TIGIT receptors inhibits their cytotoxicity, induces downregulation of IFN-γ and GZMB, and establishes a hallmark exhausted phenotype. Functional validation revealed that TRAIL knockout, exosome generation inhibition, or TIGIT blockade effectively restore NK cell activity and suppress lung metastasis, clarifying the critical role of the "TRAIL-PVR-TIGIT" axis in metastasis construction.

4, The level of extracellular TRAIL in plasma can accurately predict early postoperative pulmonary metastases

At the clinical level, the research team analyzed plasma samples from postoperative liver cancer patients to detect TRAIL levels in exosomes. They found that patients with lung metastases exhibited significantly elevated TRAIL levels, which showed a negative correlation with the expression of HK2—a key glycolysis enzyme in tumor tissues. ROC curve analysis demonstrated that plasma exosomal TRAIL demonstrated superior predictive accuracy for early-stage lung metastasis compared to traditional biomarkers such as AFP and tumor volume measurements.

RESULTS:

While "reducing sugar intake helps fight cancer" has become a golden rule in modern healthy eating, this study reveals that "sugar control" isn't always the right approach and may even aid cancer cells under certain circumstances. The findings indicate that when sugar consumption is restricted, cancer cells might release specific "signal extracellular vesicles" to preemptively modify the lung immune system. This causes immune cells to become sluggish and less vigilant, paving the way for cancer metastasis.

In other words, blindly cutting down on sugars and carbohydrates may suppress primary tumors but create opportunities for metastasis. Therefore, while dietary interventions are crucial, the true path to cancer prevention lies in personalized approaches combined with scientific evaluation.

Reference:

Wu CY, Huang CX, Lao XM, et al. Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL. Cell. Published online July 8, 2025. doi:10.1016/j.cell.2025.06.027.

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