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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
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ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING-IFN suppression

Jiaxing Ma1, Yayun Wu2, Guangzheng Lin1

  • 1Department of Urology, Second Affiliated Hospital of Anhui Medical University, Hefei, China.

Cancer Biology & Therapy
|February 20, 2026
PubMed
Abstract

Insights

Ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) is a hypoxia-induced enzyme in clear-cell renal cell carcinoma (ccRCC). Targeting ENPP3 reactivates anti-tumor immunity, offering a new therapeutic strategy for ccRCC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Clear-cell renal cell carcinoma (ccRCC) is characterized as an immune-desert tumor.
  • Ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) is investigated for its potential as a therapeutic target and immune-checkpoint enzyme in ccRCC.

Purpose of the Study:

  • To investigate the role of ENPP3 in ccRCC.
  • To analyze ENPP3 expression, its association with hypoxia and prognosis.
  • To evaluate ENPP3 as a therapeutic target, alone or in combination with anti-PD-L1 therapy.

Main Methods:

  • Analysis of ENPP3 expression and its correlation with hypoxia and prognosis in ccRCC.
  • In vitro and xenograft studies using gain/loss-of-function models.
  • Therapeutic administration of anti-ENPP3 antibodies combined with anti-PD-L1.
  • Exploration of underlying mechanisms including promoter analysis, cGAMP measurement, flow cytometry, cytokine profiling, and in vivo neutralization studies.

Main Results:

  • ENPP3 is hypoxia-inducible via HIF-1α, upregulated in ccRCC, and associated with poor prognosis.
  • ENPP3 overexpression accelerated tumor growth; its blockade inhibited progression and synergized with anti-PD-L1.
  • ENPP3 blockade increased extracellular cGAMP, enhanced anti-tumor immunity (M1 macrophages, cDC1s, cytotoxic T cells), reduced Tregs, and induced a STING- and IFNAR1-dependent type I interferon signature.

Conclusions:

  • ENPP3 acts as a hypoxia-driven, cGAMP-targeting innate immune checkpoint in ccRCC.
  • Inhibition of ENPP3 reactivates STING-dependent anti-tumor immunity.
  • Targeting ENPP3 presents a strong preclinical rationale for ccRCC therapy.
Keywords:
ENPP3cGAMP-STINGccRCCtumor-associated macrophagetype I interferon

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