Core Insights - The study reveals that glucose metabolism is a critical energy source for tumor proliferation, and targeting glucose metabolism through low-carbohydrate diets is a promising strategy to inhibit tumor growth [2][9] - However, extreme carbohydrate restriction may suppress tumor growth while simultaneously promoting lung metastasis, indicating the need for careful evaluation of metabolic intervention strategies [3][9] Mechanism of Action - Glucose deprivation induces endoplasmic reticulum (ER) stress in tumor cells, activating HRD1 to catalyze the ubiquitination of TRAIL at the K63 site, which is then packaged into exosomes [4] - These exosomes release TRAIL in the lungs, polarizing PVR⁺ macrophages and depleting lung NK cells, thus creating a favorable immune microenvironment for tumor colonization [4] Clinical Implications - The research confirms that low glucose metabolism is associated with higher recurrence rates within two years post-surgery across 15 cancer types [5] - Plasma exosomal TRAIL levels serve as an effective biomarker for predicting lung metastasis after liver cancer surgery, outperforming traditional biomarkers like alpha-fetoprotein (AFP) [6] Key Findings - Low-carbohydrate diets or impaired glucose metabolism can promote lung metastasis [7] - Glucose deprivation creates a pre-metastatic microenvironment dominated by lung macrophages [7] - Exosomal TRAIL leads to the polarization of PVR⁺ macrophages, resulting in the depletion of lung NK cells [7] - Plasma exosomal TRAIL levels can accurately predict early postoperative lung metastasis [7] Research Value - The study systematically elucidates how glucose restriction reshapes distal immune environments and promotes tumor metastasis through an exosome-immune regulatory axis, highlighting the TIGIT pathway as a potential target for combined interventions [9]