Hypoxia-induced EGR1 remodels neutrophils to suppress antitumor immunity

Abstract

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 EGR1 expression in neutrophils led to altered nuclear morphology and up-regulation of immunosuppressive factors and T cell suppression capacity. Neutrophils from Egr1-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 Egr1-deficient neutrophils restored sensitivity to immunotherapy. Pharmacologic inhibition of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway suppressed hypoxia-induced Egr1 expression and immunosuppressive capacity in neutrophils while enhancing PD-1 blockade-associated tumor control. An EGR1⁺ 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.