Hypoxia-induced EGR1 remodels neutrophils to suppress antitumor immunity

Neutrophils frequently adopt immunosuppressive phenotypes in tumors, yet the underlying mechanisms remain incompletely understood. Here, we identify the transcription factor early growth response protein 1 (EGR1) as a key regulator of nuclear morphology and immunosuppressive function in tumor-associated neutrophils. Hypoxia-induced <i>EGR1</i> expression in neutrophils led to altered nuclear morphology and up-regulation of immunosuppressive factors and T cell suppression capacity. Neutrophils from <i>Egr1</i>-deficient mice failed to undergo these hypoxia-driven pathological changes. Adoptive transfer of wild-type neutrophils into a neutrophil-deficient mouse model of oral cavity cancer conferred resistance to programmed cell death 1 (PD-1) blockade, whereas transfer of <i>Egr1</i>-deficient neutrophils restored sensitivity to immunotherapy. Pharmacologic inhibition of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway suppressed hypoxia-induced <i>Egr1</i> expression and immunosuppressive capacity in neutrophils while enhancing PD-1 blockade-associated tumor control. An <i>EGR1</i>⁺ neutrophil transcriptional signature predicted poor clinical outcomes across multiple cancer types. These findings identify EGR1 as a hypoxia-inducible driver of neutrophil-mediated immunosuppression and provide a basis for targeting the hypoxia-EGR1 axis to overcome immunotherapy resistance.