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The Role of NADPH Oxidase 4 in Neutrophil-Mediated Immune Escape in Gastric Cancer

Jinling Jiang1, Wenqi Xi1, Yanan Zheng2

  • 1Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China.

International Journal of Biological Sciences
|May 20, 2026
PubMed

Insights

NADPH oxidase 4 (NOX4) drives gastric cancer immune escape by recruiting neutrophils via GM-CSF. This promotes an immunosuppressive tumor microenvironment and resistance to anti-PD-1 therapy, suggesting targeting this axis could improve treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Biochemistry

Background:

  • NADPH oxidase 4 (NOX4) generates reactive oxygen species (ROS) and is upregulated in various cancers, including gastric cancer (GC).
  • The specific role of NOX4 in mediating immune escape within the gastric cancer microenvironment is not well understood.

Purpose of the Study:

  • To investigate the function of NOX4 in promoting immune escape in gastric cancer.
  • To elucidate the molecular mechanisms by which NOX4 influences the tumor microenvironment and neutrophil infiltration.
  • To explore the potential of targeting the NOX4 pathway for overcoming resistance to anti-PD-1 therapy.

Main Methods:

  • Analysis of NOX4 expression and neutrophil infiltration in human GC tissues and patient-derived samples.
  • Utilized in vivo functional assays in mouse models to determine the role of NOX4 and GM-CSF in neutrophil recruitment.
  • Investigated the impact of NOX4/GM-CSF signaling on neutrophil metabolic reprogramming (PHGDH, ASNS) and GC cell apoptosis.

Main Results:

  • NOX4 overexpression correlated with poor prognosis and increased neutrophil infiltration in GC patients and mouse models.
  • Tumor-derived NOX4 promotes GM-CSF secretion, which is essential for neutrophil recruitment.
  • Recruited neutrophils suppressed GC cell apoptosis and created an immunosuppressive tumor microenvironment, further enhanced by NOX4/GM-CSF signaling-mediated metabolic adaptation in neutrophils.
  • Elevated NOX4 and neutrophil infiltration were observed in GC patients resistant to neoadjuvant anti-PD-1 therapy.

Conclusions:

  • Tumor-derived NOX4 promotes GM-CSF-dependent neutrophil recruitment, leading to metabolic reprogramming and immunosuppression in gastric cancer.
  • The NOX4-GM-CSF-neutrophil axis plays a critical role in gastric cancer immune escape and resistance to immune checkpoint inhibitors.
  • Targeting the GM-CSF/neutrophil pathway presents a potential strategy to overcome resistance to anti-PD-1 therapy in gastric cancer.
Keywords:
NADPH oxidase 4gastric cancerimmune suppressionneutrophil activation

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