Targeting ENPP1: the only known checkpoint in innate immunity
Our Science
The cGAS-STING pathway is the body's primary innate immune sensor against cancer. ENPP1 is the enzyme that shuts it off. Vizenpistat is designed to block ENPP1 — reactivating innate immunity and enabling both arms of the immune system to fight back simultaneously.
How ENPP1 suppresses anti-tumor Immunity
Mechanism of Action
When cancer cells accumulate DNA damage, the body's innate immune system should detect and destroy them. ENPP1 intercepts this process, acting as a dual checkpoint that both silences the immune alarm and generates an immunosuppressive shield around the tumor.
cGAS-STING Pathway & ENPP1 Interception
cGAS detects cytoplasmic dsDNA released by damaged tumor cells and synthesizes 2’3’ cGAMP, the natural ligan that activated STING and triggers innate immune signaling.
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ENPP1 intercepts here: Before 2'3'-cGAMP can activate STING, ENPP1 degrades it into AMP and GMP — silencing the innate immune alarm. ENPP1 is highly upregulated as tumors become metastatic.
AMP is converted by CD73 into adenosine a potent immunosuppressive molecule that inhibits T-cell activity in the tumor microenvironment.
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Vizenpistat blocks ENPP1, allowing 2'3'-cGAMP to activate STING and restore innate immune signaling, enabling both arms of immunity to mount a coordinated anti-tumor response.
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Clinical Consequences of ENPP1 Overexpression
Reduced immune infiltration
High ENPP1 correlates with immune-cold tumors, known for fewer T-cells and NK cells able to penetrate the tumor microenvironment
Increased metastatic potential
ENPP1 upregulation is strongly associated with metastatic progression and immune evasion as tumors spread
Resistance to chemotherapy
High ENPP1 correlates with reduced sensitivity to chemotherapeutic agents
Half of all cancers are affected
ENPP1 upregulation spans a broad range of solid tumor types — A vast addressable population
Resistance to checkpoint inhibitors
Tumors with high ENPP1 are resistant to PD-1 /CTLA-4 blockade
Key Literature
Peer-reviewed Evidence for eNPP1 as an oncology target
Biochem Pharmacology — 2024
Targeting ENPP1 for cancer immunotherapy: Killing two birds with one stone
Huang R, Ning Q, Zhao J, et al.
Cancer Discovery — 2021
Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis
Li J, Duran MA, Dhanota N, et al.
PNAS — 2023
ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway in breast cancer
Wang S, Böhnert V, Joseph AJ, et al.
Oncology Letters — 2024
Role of ENPP1 in cancer pathogenesis: Mechanisms and clinical implications (Review)
Zhao L, Zhang Y, Tian Y, et al.