ArticleCancer research2022
A Novel Selective Inhibitor JBI-589 Targets PAD4-Mediated Neutrophil Migration to Suppress Tumor Progression.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 2 of them syntheses that pooled it.
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Who cites it
66 citing papers in PubMed, 2 syntheses or guidelines pooled it, 73 citations in OpenAlex.
- From immunological mechanisms to targeted therapies: a bibliometric analysis in the domain of research concerning neutrophil extracellular traps and pulmonary diseases (2006-2025).Frontiers in immunology · 2026Pooled it
- Research trends on neutrophil extracellular traps in ischemic stroke: a scientific metrology study.Frontiers in pharmacology · 2025Pooled it
- Deubiquitinase USP48 Promotes Gastric Cancer Peritoneal Metastasis by Stabilizing S100A9 to Drive Neutrophil Extracellular Traps Formation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- PAD4-DB: A Curated Structure-Activity Resource Reveals Hub-Organized Activity Cliffs and Scaffold-Dependent SAR Ruggedness in PAD4 Inhibitors.International journal of molecular sciences · 2026Article
- Neutrophil Extracellular Traps in the Tumor Microenvironment: Mechanisms, Immune Regulation, and Implications for Immune Checkpoint Inhibitor Therapy.International journal of molecular sciences · 2026Review
- Neutrophils in cancer.Nature reviews. Cancer · 2026Review
- From Bone Marrow Reserve to Metastatic Niche: How Neutrophil-Lineage Cells Shape Skeletal Colonization.International journal of molecular sciences · 2026Review
- Targeting neutrophil extracellular traps (NETs): a promising immunotherapeutic approach for pulmonary diseases.Molecular biology reports · 2026Review
- The Neutrophil-NET Axis in Immune Checkpoint Inhibitor Resistance in Non-Small Cell Lung Cancer: Roles, Biomarkers and Therapeutic Opportunities.Biomolecules · 2026Review
- Neutrophils in glioblastoma: orchestrators of the tumor microenvironment and immune evasion.Molecular biology reports · 2026Review
- Neutrophil extracellular traps in cancer.Nature reviews. Cancer · 2026Review
- Interleukin-33 Promotes Neutrophil Extracellular Trap Formation To Aggravate Renal Ischemia-Reperfusion Injury Through ST2/PI3K/Akt and ST2/PAD4 Pathways.Inflammation · 2026Article
- Citrullination Accompanies the Development of Carotid Atherosclerotic Plaques.Current medicinal chemistry · 2026Article
- Neutrophil extracellular traps: the hidden driver of gastrointestinal cancer and emerging therapeutic strategies.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps induce chemoresistance in human breast cancer cells through the PI3K/AKT/NF-κB pathway.Frontiers in immunology · 2026Article
- Neutrophils and neutrophil extracellular traps in ischaemia-reperfusion injury: pathophysiological roles and therapeutic potential.Burns & trauma · 2026Review
- Neutrophil Extracellular Traps in Diabetic Kidney Disease: Mechanisms of Pathogenesis and Emerging Therapeutic Strategies.Drug design, development and therapy · 2026Review
- Targeting neutrophil-driven immunosuppression: A strategy to overcome immune checkpoint inhibitor resistance.Clinical and translational medicine · 2026Review
- Neutrophil extracellular traps in colorectal cancer: a paradoxical nexus of tumor defense and disease progression.Frontiers in immunology · 2026Review
- The role and mechanism of neutrophils in oncolytic virus therapy.Experimental biology and medicine (Maywood, N.J.) · 2026Review
6 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 5 institutions in 1 country.
Funding
Abstract
Neutrophils are closely involved in the regulation of tumor progression and formation of premetastatic niches. However, the mechanisms of their involvement and therapeutic regulation of these processes remain elusive. Here, we report a critical role of neutrophil peptidylarginine deiminase 4 (PAD4) in neutrophil migration in cancer. In several transplantable and genetically engineered mouse models, tumor growth was accompanied by significantly elevated enzymatic activity of neutrophil PAD4. Targeted deletion of PAD4 in neutrophils markedly decreased the intratumoral abundance of neutrophils and led to delayed growth of primary tumors and dramatically reduced lung metastases. PAD4-mediated neutrophil accumulation by regulating the expression of the major chemokine receptor CXCR2. PAD4 expression and activity as well as CXCR2 expression were significantly upregulated in neutrophils from patients with lung and colon cancers compared with healthy donors, and PAD4 and CXCR2 expression were positively correlated in neutrophils from patients with cancer. In tumor-bearing mice, pharmacologic inhibition of PAD4 with the novel PAD4 isoform-selective small molecule inhibitor JBI-589 resulted in reduced CXCR2 expression and blocked neutrophil chemotaxis. In mouse tumor models, targeted deletion of PAD4 in neutrophils or pharmacologic inhibition of PAD4 with JBI-589 reduced both primary tumor growth and lung metastases and substantially enhanced the effect of immune checkpoint inhibitors. Taken together, these results suggest a therapeutic potential of targeting PAD4 in cancer. SIGNIFICANCE: PAD4 regulates tumor progression by promoting neutrophil migration and can be targeted with a small molecule inhibitor to suppress tumor growth and metastasis and increase efficacy of immune checkpoint blockade therapy.
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Registered trials
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.