Metabolic Reprogramming of the Pre‐Metastatic Niche: A Sweet Spot for Anti‐Tumor Immunity

In a research article published in Cell, Wu et al. revealed a critical paradox: Glucose restriction inhibits primary tumor growth while promoting metastasis 1. The research systematically delineates the mechanism by which glucose deprivation promotes lung metastasis, laying the theoretical foundation for combined metabolic reprogramming and immunotherapy. The proliferation of tumor cells is highly dependent on glucose metabolism 2. Previous studies have demonstrated that targeting glucose metabolism can activate apoptotic signaling pathways in cancer cells, thereby inhibiting malignant tumor proliferation 3. However, metastasis, rather than primary tumor growth, is the principal cause of cancer-related deaths. Two key findings were achieved: First, in distant metastatic sites such as the lungs, glucose deprivation can cause macrophage-mediated natural killer (NK) cell exhaustion through the poliovirus receptor (PVR)-T cell immunoreceptor with Ig and ITIM domains (TIGIT) axis, forming a pre-metastatic niche (PMN) conducive to tumor metastasis; Second, in primary tumors, there is a regulatory relationship between glucose deprivation and exosomal tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and it is revealed that exosomal TRAIL has a non-classical effect. Genetic Set Variation Analysis (GSVA) of clinical data showed a significant association between low glucose metabolism and increased 2-year postoperative recurrence rates across 15 cancer types, most notably in hepatocellular carcinoma (HCC) 1. In this study, models of glucose restriction were established using a low-carbohydrate (LC) diet and impaired glucose metabolism. Using multiple tumor mouse models, it was concluded that although glucose deficiency induced by an LC diet inhibits primary tumor growth, it unexpectedly elevated the risk of lung metastasis (Figure 1A). Conversely, glutamine deprivation did not significantly promote metastasis in HCC. Notably, unlike high-carbohydrate (HC) diets, lung metastasis induced by LC diets was unrelated to increased primary tumor volume 1. Further research suggested that enhanced metastasis under glucose restriction was attributable to PMN formation rather than enhanced invasiveness of cancer cells. The formation of the PMN in distant organs is a critical step in the development of metastasis, as it creates an environment that supports the colonization of tumor cells. While previous studies have primarily focused on pro-tumor factors such as fibronectin and vascular endothelial growth factor 4, the authors adopted a novel metabolic perspective to investigate the role of glucose deprivation in the establishment of the PMN. They found that glucose deprivation in the primary tumor established PMNs in the lungs, characterized by macrophage-dependent NK cell exhaustion and functional impairment. Notably, the LC diet only slightly influences adaptive immune cells, such as CD4+ T cells, CD8+ T cells and B cells 1. In order to investigate how pulmonary macrophages induce NK cell depletion, the authors found a key immunosuppressive axis-the PVR-TIGIT interaction axis-by single-cell sequencing. In the lung macrophages of Hepa1-6 tumor-bearing mice, PVR was identified as a critical NK-inhibitory ligand. Its expression was the most significantly upregulated, primarily in F4/80+ macrophages. Meanwhile, TIGIT, an inhibitory immune checkpoint receptor, is mainly expressed on NK cells and T cells. Subsequent experiments confirmed that PVR+ macrophages transmitted strong inhibitory signals when they interacted with TIGIT+ NK cells. Functional experiments demonstrated that blocking TIGIT signaling under glucose deprivation conditions not only restores NK cell numbers and function but also significantly suppresses lung metastasis and promotes regression of the primary tumor. Exosomes, nanoscale extracellular vesicles, are key mediators of intercellular communication. As a member of the tumor necrosis factor (TNF) superfamily, TRAIL is famous for its ability to trigger cancer cell apoptosis. However, how it regulates immune cells such as NK cells and macrophages is not fully understood 5. In conditions of glucose deprivation, Hepa1-6 cells released exosomes loaded with TRAIL 1. In terms of mechanism, glucose deprivation triggers endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1). HRD1 then acts as catalyst for K63-linked ubiquitination of TRAIL. Subsequently, the ubiquitinated TRAIL is packed into exosomes through the endosomal sorting complex required for transport (ESCRT) pathway and released into the space outside the cell. These TRAIL-rich exosomes travel through the bloodstream to the lungs. In the lungs, TRAIL targets PVR⁺ macrophages by binding to TRAIL receptors (TNFRSF10B) on their surface. This binding ultimately activates the nuclear factor κB (NF-κB) signaling pathway. Activation of this pathway results in two key events: the release of inflammatory mediators including tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β as well as the specific upregulation of PVR on the macrophage surface (Figure 1B). The elevated PVR expression then interacts with the inhibitory receptor TIGIT on the surface of NK cells. This interaction leads to NK cell exhaustion and ultimately promotes the formation of PMNs in the lungs. This is the first study to unveil the non-classical function of TRAIL in inducing NK cell exhaustion via exosomes. The functional change of TRAIL is closely related to glucose deprivation. Glucose deprivation activates the “ER stress-HRD1-Ub-ESCRT-exosome” axis, transforming TRAIL from a soluble molecule into a remotely delivered exosomal membrane signaling molecule. Consequently, the target cells for exosomal TRAIL shift from tumor cells expressing its classical death receptors to macrophages. The predictive model showed that plasma TRAIL-positive exosomes are superior to traditional indicators including α-fetoprotein levels as well as tumor volume in accurately forecasting lung metastasis during the early postoperative stage 1. For patients with HCC exhibiting raised levels of plasma TRAIL-enriched exosomes, targeting TIGIT treatment may effectively offset the effect of fostering metastasis caused by glucose deprivation. Combining anti-TIGIT therapy with targeting tumor glucose metabolism may be a promising approach to personalized treatment. Although this work innovatively presented the glucose deprivation paradox, there are still some limitations. First, the study focused primarily on HCC. It remains unclear whether these findings apply to other cancer types beyond HCC, particularly those characterized by high glycolysis. Therefore, further exploration of this mechanism in other cancer models is necessary. Second, apart from lung metastasis, it is currently unclear whether the TRAIL-PVR/TIGIT axis plays a similar regulatory role in other common metastasis sites, such as the liver and bones. Moreover, although this study proposed that plasma exosomal TRAIL may be a promising predictive biomarker, its clinical application value requires large-scale cohort studies to support it. Overall, Wu et al. revealed the pivotal paradoxical phenomenon of glucose deprivation inhibits primary tumor growth while fostering lung metastasis, identifying and validating the “glucose deprivation-TRAIL-PVR/TIGIT” signaling axis. More importantly, this study provides a novel promising therapeutic target-anti-TIGIT therapy-for strategies targeting the pre-metastatic microenvironment. It stands as a seminal contribution integrating cancer metabolism, exosome biology and tumor immunology. Xuan Zhang: visualization, writing – original draft, writing – review and editing. Xinghua Long: conceptualization, funding acquisition, supervision, writing – original draft, writing – review and editing. Both authors have read and approved the final manuscript. This work was supported by grants from National Natural Science Foundation of China (81272372) and by Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund (PTXM2022017). The figure was created by BioRender. The authors declare no conflicts of interest. The authors have nothing to report.