Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 8:S0092-8674(25)00728-7.
doi: 10.1016/j.cell.2025.06.027. Online ahead of print.

Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL

Cai-Yuan Wu  1 , Chun-Xiang Huang  1 , Xiang-Ming Lao  2 , Zi-Wen Zhou  1 , Jia-Hong Jian  1 , Zheng-Xi Li  1 , Yong-Yi Wu  1 , Zheng-Yu Liu  1 , Lei Chen  3 , Lianxin Liu  4 , Limin Zheng  1 , Yuan Wei  5 , Dong-Ming Kuang  6
Affiliations

Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL

Cai-Yuan Wu et al. Cell. .

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.

Keywords: NK cell; exosomal TRAIL; low-carbohydrate diet; lung metastasis; macrophage.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Similar articles

  • Short-Term Memory Impairment.
    Cascella M, Al Khalili Y. Cascella M, et al. 2024 Jun 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. 2024 Jun 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 31424720 Free Books & Documents.
  • M1 Macrophage-Derived TNF-α Promotes Pancreatic Cancer Ferroptosis Via p38 MAPK-ACSL4 Pathway.
    Zhang JC, Yin HL, Chen QD, Zhao GC, Pu N, Lou WH, Wu WC. Zhang JC, et al. Curr Mol Med. 2025 Jul 10. doi: 10.2174/0115665240374551250630075409. Online ahead of print. Curr Mol Med. 2025. PMID: 40653839
  • Management of urinary stones by experts in stone disease (ESD 2025).
    Papatsoris A, Geavlete B, Radavoi GD, Alameedee M, Almusafer M, Ather MH, Budia A, Cumpanas AA, Kiremi MC, Dellis A, Elhowairis M, Galán-Llopis JA, Geavlete P, Guimerà Garcia J, Isern B, Jinga V, Lopez JM, Mainez JA, Mitsogiannis I, Mora Christian J, Moussa M, Multescu R, Oguz Acar Y, Petkova K, Piñero A, Popov E, Ramos Cebrian M, Rascu S, Siener R, Sountoulides P, Stamatelou K, Syed J, Trinchieri A. Papatsoris A, et al. Arch Ital Urol Androl. 2025 Jun 30;97(2):14085. doi: 10.4081/aiua.2025.14085. Epub 2025 Jun 30. Arch Ital Urol Androl. 2025. PMID: 40583613 Review.
  • Systemic treatments for metastatic cutaneous melanoma.
    Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S. Pasquali S, et al. Cochrane Database Syst Rev. 2018 Feb 6;2(2):CD011123. doi: 10.1002/14651858.CD011123.pub2. Cochrane Database Syst Rev. 2018. PMID: 29405038 Free PMC article.
  • The Black Book of Psychotropic Dosing and Monitoring.
    DeBattista C, Schatzberg AF. DeBattista C, et al. Psychopharmacol Bull. 2024 Jul 8;54(3):8-59. Psychopharmacol Bull. 2024. PMID: 38993656 Free PMC article. Review.
See all similar articles

LinkOut - more resources