Evidence map›Paper›PMID 38749434›Full record

ArticleCell reports2024

Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint.

Rachel Mardjuki, Songnan Wang, Jacqueline Carozza, Bahar Zirak, Vishvak Subramanyam, Gita Abhiraman, Xuchao Lyu, Hani Goodarzi, Lingyin Li

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

27 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
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  5. Review
  6. Article
  7. Extracellular cGAMP in health and disease.Molecular biomedicine · 2026
    Review
  8. Article
  9. Review
  10. Review
  11. Article
  12. Review
  13. Article
  14. Review
  15. Review
  16. Article
  17. Review
  18. Article
  19. Article
  20. cGAS-STING: mechanisms and therapeutic opportunities.Science China. Life sciences · 2025
    Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Rachel MardjukiDepartment of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Songnan WangDepartment of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA.
Jacqueline CarozzaArc Institute, Palo Alto, CA 94304, USA.
Bahar ZirakArc Institute, Palo Alto, CA 94304, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biophysics & Biochemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Baker Computational Health Science Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Vishvak SubramanyamArc Institute, Palo Alto, CA 94304, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biophysics & Biochemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Baker Computational Health Science Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Gita AbhiramanDepartment of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
Xuchao LyuChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Hani GoodarziArc Institute, Palo Alto, CA 94304, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biophysics & Biochemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Baker Computational Health Science Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Lingyin LiDepartment of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: lingyin@arcinstitute.org.

Funding

Translational Oncology Research Program (Project-005)P30CA124435 · NCI · STANFORD UNIVERSITY · PI Vittorio Sebastiano · 2007 to 2026
$71.4M
NCI NIH HHS P30 CA124435
6 · The paper itself

Abstract

2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for cancer immunotherapy.

Indexed as

Immunity, InnateMembrane ProteinsNucleotides, CyclicPhosphoric Diester HydrolasesPyrophosphatasesAnimalsHumansHydrolysisMiceMice, Inbred C57BLNeoplasmsSignal TransductionSTING Proteincyclic guanosine monophosphate-adenosine monophosphateectonucleotide pyrophosphatase phosphodiesterase 1ENPP3 protein, humanMembrane ProteinsNucleotides, CyclicPhosphoric Diester HydrolasesPyrophosphatasesSting1 protein, mouseSTING Proteinbreast cancercGAMPclinical trialCP: ImmunologyENPP1ENPP3hydrolaseimmune checkpointmelanomaPD-1STING

Identifiers

PMID38749434
PMCPMC13268100

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.