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

NADPH oxidase 4 (NOX4) transmits electrons for various redox reactions by generating reactive oxygen species (ROS), which are present at high levels in a variety of malignant tumors, including gastric cancer (GC). Nevertheless, the role of NOX4 in inducing immune escape in GC remains unknown. We analyzed the correlation between NOX4 expression and infiltrating neutrophils in human GC tissue. NOX4 overexpression correlated with poor prognosis and enhanced neutrophil infiltration in GC patients and mouse models. Tumor-derived NOX4 promoted secretion of GM-CSF, which was established through in vivo functional assays as the key factor responsible for neutrophil recruitment. Recruited neutrophils inhibited GC cell apoptosis and fostered an immunosuppressive microenvironment. NOX4/GM-CSF signaling further enhanced PHGDH and ASNS-mediated metabolic adaptation in neutrophils. Elevated NOX4 and neutrophil infiltration were observed in GC patients unresponsive to neoadjuvant anti-PD-1 therapy. Tumor-derived NOX4 drives GM-CSF-dependent neutrophil recruitment, leading to metabolic reprogramming and immunosuppression in GC. Targeting the GM-CSF/neutrophil axis may overcome resistance to immune checkpoint inhibitors.