ArticleNature communications2025
Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- SEVs-carried ENPP1 regulates DCs' activation and inhibits the formation of tertiary lymphoid structures in gastric cancer.Journal of gastroenterology · 2026Article
- Senkyunolide I Inhibits mtDNA-cGAS-STING Signaling in Macrophages via Targeting VDAC1 Oligomerization to Attenuate Ulcerative Colitis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential.The Journal of clinical investigation · 2026Review
- Therapeutic targeting of the cGAS-STING pathway in human disease.The Journal of clinical investigation · 2026Review
- Molecular mechanisms regulating cGAS/STING activation in health and disease.The Journal of clinical investigation · 2026Review
- Striking the right balance with type I interferon signalling in cancer.Nature reviews. Cancer · 2026Review
- The Expanding Landscape of ADP-Ribosylation: Protein, DNA, RNA, and Mitochondrial Regulation.Chemical research in toxicology · 2026Review
- Extracellular cGAMP in health and disease.Molecular biomedicine · 2026Review
- Precision targeting of STING: Challenges, innovations, and clinical outlook for cancer therapy.Innovation (Cambridge (Mass.)) · 2026Review
- Artificial intelligence based quantification of T lymphocyte infiltrate predicts prognosis in high grade breast cancer using deep learning and statistical validation.Discover oncology · 2025Article
- JUN-ENPP1-cGAS-STING axis mediates immune evasion and tumor progression in bladder cancer.Journal of translational medicine · 2025Article
- Breaking barriers: The cGAS-STING pathway as a novel frontier in cancer immunotherapy.Cancer communications (London, England) · 2025Review
- The cGAS‒STING pathway in colorectal cancer: bridging innate immunity and therapeutic strategies.Journal of experimental & clinical cancer research : CR · 2025Review
- Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors.Nature communications · 2025Article
- Adenosine receptors on the immuno-oncology expressway: TIME, perspectives, and translation.Frontiers in immunology · 2025Review
- Novel nanobody-161 binds tumor necrosis factor receptor 2 (TNFR2) to exert an anti-tumor effect but does not block TNFα-binding.Frontiers in immunology · 2025Article
Corrections and comments
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite the STING-type-I interferon pathway playing a key role in effective anti-tumor immunity, the therapeutic benefit of direct STING agonists appears limited. In this study, we use several artificial intelligence techniques and patient-based multi-omics data to show that Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), which hydrolyzes STING-activating cyclic GMP-AMP (cGAMP), is a safer and more effective STING-modulating target than direct STING agonism in multiple solid tumors. We then leverage our generative chemistry artificial intelligence-based drug design platform to facilitate the design of ISM5939, an orally bioavailable ENPP1-selective inhibitor capable of stabilizing extracellular cGAMP and activating bystander antigen-presenting cells without inducing either toxic inflammatory cytokine release or tumor-infiltrating T-cell death. In murine syngeneic models across cancer types, ISM5939 synergizes with targeting the PD-1/PD-L1 axis and chemotherapy in suppressing tumor growth with good tolerance. Our findings provide evidence supporting ENPP1 as an innate immune checkpoint across solid tumors and reports an AI design-aided ENPP1 inhibitor, ISM5939, as a cutting-edge STING modulator for cancer therapy, paving a path for immunotherapy advancements.
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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.