Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis PMID: 33372007

RQC and Longevity Regulation

2026-09-03

Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis

Cancer Discov. 2021 May;11(5):1212-1227. doi: 10.1158/2159-8290.CD-20-0387.

Jun Li ^# ¹ ² , Mercedes A Duran ^# ¹ ² , Ninjit Dhanota ¹ ² , Walid K Chatila ¹ ³ , Sarah E Bettigole ⁴ , John Kwon ¹ ² , Roshan K Sriram ⁵ , Matthew P Humphries ⁶ , Manuel Salto-Tellez ⁶ ⁷ , Jacqueline A James ⁶ , Matthew G Hanna ⁸ , Johannes C Melms ⁹ ¹⁰ , Sreeram Vallabhaneni ¹¹ , Kevin Litchfield ¹² , Ieva Usaite ¹² , Dhruva Biswas ¹² , Rohan Bareja ¹³ , Hao Wei Li ⁹ , Maria Laura Martin ¹³ , Princesca Dorsaint ¹³ , Julie-Ann Cavallo ¹ ² , Peng Li ¹⁴ , Chantal Pauli ¹⁵ , Lee Gottesdiener ¹⁶ , Benjamin J DiPardo ¹⁷ , Travis J Hollmann ⁷ , Taha Merghoub ¹ ¹⁶ ¹⁸ ¹⁹ ²⁰ , Hannah Y Wen ⁸ , Jorge S Reis-Filho ⁸ , Nadeem Riaz ² , Shin-San Michael Su ⁴ , Anusha Kalbasi ²¹ , Neil Vasan ¹⁶ ¹⁸ , Simon N Powell ² , Jedd D Wolchok ¹ ¹⁶ ¹⁸ ¹⁹ ²⁰ , Olivier Elemento ¹³ , Charles Swanton ¹² , Alexander N Shoushtari ¹⁶ ¹⁸ , Eileen E Parkes ^# ⁶ ⁷ , Benjamin Izar ^# ⁹ ¹⁰ , Samuel F Bakhoum ²² ²

Affiliations

1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
3. Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, New York.
4. Volastra Therapeutics Inc., New York, New York.
5. Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
6. Precision Medicine Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
7. Medical Sciences Division, Department of Oncology, University of Oxford, Oxford, United Kingdom.
8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
9. Columbia Center for Translational Immunology, New York, New York.
10. Division of Hematology and Oncology, Columbia University Medical Center, New York, New York.
11. Laboratory for Systems Pharmacology, Harvard Medical School, Boston, Massachusetts.
12. Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, United Kingdom.
13. Englander Institute for Precision Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
14. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
15. Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
16. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
17. Department of Surgery, University of California, Los Angeles, California.
18. Department of Medicine, Weill Cornell Medicine, New York, New York.
19. Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
20. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.
21. Department of Radiation Oncology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
22. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected].
# Contributed equally.

Abstract

Cytosolic DNA is characteristic of chromosomally unstable metastatic Cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How Tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor Adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular Adenosine, and renders otherwise sensitive Tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable Tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from Cancer cells to immune cells.This article is highlighted in the In This Issue feature, p. 995.