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NETs Promote Cancer Progression And Immune Evasion

Tumor Microenvironment Chronic Inflammation Cancer Immunotherapy

Neutrophil extracellular traps, or NETs, are extracellular DNA-protein structures released by activated neutrophils and originally described as a host-defense mechanism against bacteria. Cancer research later repositioned NETs as tumor microenvironment regulators because malignant cells and tumor-associated inflammation can induce NETosis, and NETs can support metastatic seeding, tumor growth, thrombosis, and immune escape. NET biology is now central to cancer progression because it links innate inflammation, neutrophil activation, extracellular chromatin, proteases, and failed antitumor immunity[1][2][3].

Mechanistically, NETs promote metastasis by trapping circulating tumor cells, increasing tumor-cell adhesion, and remodeling tissue niches. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps, and NETs sequester circulating tumor cells under static and dynamic conditions. During sustained inflammation, NET-associated neutrophil elastase and MMP9 remodel laminin, activate integrin α3β1 signaling, and awaken dormant cancer cells. NET-DNA also binds CCDC25 on cancer cells and activates ILK-β-parvin signaling, providing a direct DNA-sensing route to metastasis[2][3][4][5][6].

NETs also promote immune evasion by forming physical and metabolic barriers against cytotoxic immunity. Tumor-produced CXCR1 and CXCR2 agonists induce NETs that interfere with immune cytotoxicity, and NETs can shield tumor cells from CD8+ T-cell and NK-cell killing. NETs promote T-cell exhaustion in cancer and suppress T-cell responses through metabolic and functional exhaustion. NET-associated ARG1 further supports immune suppression in pancreatic cancer by depleting arginine and inhibiting T-cell activation[7][8][9].

Disease applications now focus on NET biomarkers, DNase-based NET degradation, PAD4 or neutrophil elastase inhibition, CXCR1/CXCR2 blockade, CCDC25 targeting, ARG1 inhibition, and combinations with immune checkpoint blockade. Key gaps include distinguishing protective antimicrobial NETs from tumor-promoting NETs, validating NET biomarkers in patients, and avoiding host-defense toxicity. Future cancer immunotherapy should integrate NET mapping with neutrophil states, spatial tumor immunology, thrombosis risk, metastasis surveillance, and rational combinations that dismantle NET-mediated immune shielding while preserving essential neutrophil defense[1][4][6][7][8][9].

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Cat. No. Product Name Information Application Publication
HY-100941 CCCP
CCCP is an oxidative phosphorylation (OXPHOS) uncoupler. CCCP induces activation of PINK1 leading to Parkin Ser65 phosphorylation.
PINK1/Parkin   Oxidative Phosphorylation   STING   IFNAR   Mitochondrial Metabolism   Bacterial   Apoptosis  
Non-Small Cell Lung Cancer   Mycobacterium Tuberculosis Infection   Parkinson's Disease  
193
HY-112693 H-151
H-151 is a potent, selective and covalent antagonist of STING that has noteworthy inhibitory activity both in cells and in vivo. H-151 reduces TBK1 phosphorylation and suppresses STING palmitoylation. H-151 can be used for the research of autoinflammatory disease.
STING  
Cancer   Inflammation or Immune System Disease  
169
HY-112906 C-176
C-176 is a selective and blood-brain barrier permeable STING inhibitor. C-176 covalently targets transmembrane cysteine residue 91 and thereby blocking activation-induced palmitoylation of STING.
STING  
Cancer   Neurological, Eye or Ear Disease   Inflammation or Immune System Disease  
128
HY-50912 Plerixafor octahydrochloride
Plerixafor octahydrochloride (AMD3100 octahydrochloride) is a selective CXCR4 antagonist with an IC50 of 44 nM.
CXCR   HIV   Virus Protease  
Pancreatic Cancer   Viral Infection   Digestive System Inflammation   Glucose Metabolism   SARS-CoV-2 Infection   Lung Fibrosis   Rheumatoid Arthritis  
113
HY-10046 Plerixafor
Plerixafor (AMD 3100) is a selective CXCR4 antagonist with an IC50 of 44 nM. Plerixafor, an immunostimulant and a hematopoietic stem cell (HSC) mobilizer, is an allosteric agonist of CXCR7. Plerixafor inhibits HIV-1 and HIV-2 replication with an EC50 of 1-10 nM.
CXCR   HIV  
Pancreatic Cancer   Viral Infection   Digestive System Inflammation   Glucose Metabolism   SARS-CoV-2 Infection   Lung Fibrosis   Rheumatoid Arthritis  
113
HY-10964 Vadimezan
Vadimezan (DMXAA), the tumor vascular disrupting agent (tumor-VDA), is a murine agonist of the stimulator of interferon genes (STING) and also a potent inducer of type I IFNs and other cytokines. Vadimezan is unable to activate human STING. Vadimezan has anti-influenza virus H1N1-PR8 activities.
STING   IFNAR   Influenza Virus  
Prostate Cancer   Viral Infection   Autoimmune Disease   Non-Small Cell Lung Cancer  
81
HY-16711 SB225002
SB225002, a potent, selective and non-peptide CXCR2 antagonist, inhibits 125I-IL-8 binding to CXCR2 with an IC50 of 22 nM.
CXCR  
Metabolic or Endocrine Disease   Gastric Cancer   Digestive System Inflammation   Rheumatoid Arthritis  
66
HY-15251 Reparixin
Reparixin is a non-competitive allosteric inhibitor of the chemokine receptors CXCR1 and CXCR2 activation with IC50s of 1 and 100 nM, respectively.
CXCR  
Metabolic or Endocrine Disease   Gastric Cancer   Pancreatic Cancer   Digestive System Inflammation   Rheumatoid Arthritis  
65
HY-112921A diABZI STING agonist-1
diABZI STING agonist-1 is a tautomerism of diABZI STING agonist-1 tautomerism (HY-112921). diABZI STING agonist-1 is a selective stimulator of interferon genes (STING) receptor agonist, with EC50s of 130, 186 nM for human and mouse, respectively.
STING  
Cancer   Inflammation or Immune System Disease   Neurodegenerative Disease  
52
HY-100564A 2',3'-cGAMP sodium
2',3'-cGAMP sodium (2'-3'-cyclic GMP-AMP sodium) is a endogenous cGAMP in mammalian cells. 2',3'-cGAMP sodium binds to STING with a high affinity and is a potent inducer of interferon-β (IFNβ). 2',3'-cGAMP sodium is produced in mammalian cells in response to DNA in the cytoplasm.
Endogenous Metabolite   STING   IFNAR  
Metabolic or Endocrine Disease  
44
HY-100564 2',3'-cGAMP
2',3'-cGAMP (2'-3'-cyclic GMP-AMP) is a endogenous cGAMP in mammalian cells. 2',3'-cGAMP binds to STING with a high affinity and is a potent inducer of interferon-β (IFNβ). 2',3'-cGAMP is produced in mammalian cells in response to DNA in the cytoplasm.
Endogenous Metabolite   STING   IFNAR  
Metabolic or Endocrine Disease  
44
HY-15319 AMG 487
AMG 487 is an orally active and selective antagonist of CXC chemokine receptor 3 (CXCR3) which inhibits the binding of CXCL10 and CXCL11 to CXCR3 with IC50s of 8.0 and 8.2 nM, respectively.
CXCR  
Cancer   Metabolic or Endocrine Disease   Digestive System Disease   Digestive System Inflammation   Rheumatoid Arthritis  
40
HY-136927 MSA-2
MSA-2, a potent and orally available non-nucleotide STING agonist, is bound to STING as a noncovalent dimer with nanomolar affinity. MSA-2 shows EC50s of 8.3 and 24 μM for human STING isoforms WT and HAQ, respectively. MSA-2 stimulates interferon-β secretion in tumors, induces tumor regression with durable antitumor immunity, and synergizes with anti-PD-1 in syngeneic mouse tumor models.
STING  
Cancer   Inflammation or Immune System Disease  
35
HY-10198 Navarixin
Navarixin (SCH 527123) is a potent, allosteric and orally active antagonist of both CXCR1 and CXCR2, with Kd values of 41 nM for cynomolgus CXCR1 and 0.20 nM, 0.20 nM, 0.08 nM for mouse, rat and cynomolgus monkey CXCR2, respectivelly.
CXCR  
Metabolic or Endocrine Disease   Prostate Cancer   Gastric Cancer   Digestive System Inflammation   SARS-CoV-2 Infection   Rheumatoid Arthritis  
32
HY-13902 Berzosertib
Berzosertib (VE-822) is an orally active, CNS-penetrant, and selective ATR kinase inhibitor. Berzosertib blocks ATR kinase activity, abrogates G2/M cell cycle checkpoint, impairs DNA damage repair. Berzosertib induces apoptosis, inhibnits conlony migration, inhibits cell proliferation, and activates cGAS-STING axes in cancer cells. Berzosertib can be used for the research of cancers, such as head and neck squamous cell carcinoma, and colorectal cancer.
ATM/ATR   Apoptosis   STING   Caspase  
Pancreatic Cancer   Ovarian Cancer   SARS-CoV-2 Infection   Obesity  
27
HY-13848 Rugocrixan
AZD8797 (KAND567) is an allosteric non-competitive and orally active antagonist of the human CX3CR1 receptor; antagonizes CX3CR1 and CXCR2 with Kis of 3.9 and 2800 nM, respectively.
CX3CR1   CXCR  
Cancer   Metabolic or Endocrine Disease   Digestive System Disease   Digestive System Inflammation  
26
HY-12212 Omaveloxolone
Omaveloxolone (RTA 408) is an antioxidant inflammation modulator (AIM), which activates Nrf2 and suppresses nitric oxide (NO). Omaveloxolone attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling.
Keap1-Nrf2   STING   Apoptosis  
Cancer   Digestive System Disease   Digestive System Inflammation   Obesity   Lung Fibrosis  
26
HY-13406 TAK-779
TAK-779 is a potent and selective nonpeptide antagonist of CCR5 and CXCR3, with a Ki of 1.1 nM for CCR5, and effectively and selectively inhibits R5 HIV-1, with EC50 and EC90 of 1.2 nM and 5.7 nM, respectively, in MAGI-CCR5 cells.
CCR   HIV   CXCR  
Cancer   Metabolic or Endocrine Disease   Digestive System Disease   Viral Infection   Digestive System Inflammation   Lung Fibrosis   Rheumatoid Arthritis  
13
HY-19855 AZD-5069
AZD-5069 is a potent CXCR2 chemokine receptor antagonist, used for caner treatment.
CXCR  
Metabolic or Endocrine Disease   Prostate Cancer   Gastric Cancer   Pancreatic Cancer   Digestive System Inflammation   Rheumatoid Arthritis  
12
HY-100806 Kynurenic acid
Kynurenic acid, an endogenous tryptophan metabolite, is a broad-spectrum antagonist targeting NMDA, glutamate, α7 nicotinic acetylcholine receptor. Kynurenic acid is also an agonist of GPR35/CXCR8.
iGluR   Endogenous Metabolite   Apoptosis   CXCR   GPR35  
Metabolic or Endocrine Disease   Colorectal Cancer   Depression   Digestive System Inflammation   Non-Small Cell Lung Cancer   Alzheimer's Disease   Parkinson's Disease  
11

Keywords

NETs, neutrophil extracellular traps, NETosis, cancer progression, metastasis, immune evasion, CCDC25, CXCR1, CXCR2, T-cell exhaustion, tumor microenvironment