STING reprogramming by estrogen promotes neutrophil extracellular trap formation and sex-biased resistance to ADC therapy.

Estrogen-driven activation of STING signaling promotes neutrophil extracellular trap formation, causing female-biased resistance to ADC therapy in pancreatic cancer models.

• Why it matters: Understanding sex differences in cancer therapy response is crucial because they may influence treatment effectiveness and patient outcomes. Despite similar antigen expression, females show resistance to CLDN18.2-targeted ADC therapy, highlighting a gap in knowledge about underlying mechanisms.
• What they did: Researchers used a preclinical trial with 55 patient-derived xenografts of pancreatic cancer to compare responses between sexes, focusing on estrogen's role in modulating tumor immune signaling pathways.
• The result: The study found that estrogen signaling via GPER1 upregulates TRAF6, shifting STING activity toward NF-κB activation, which promotes NET formation that impairs ADC access, and disrupting NETs with sivelestat improved therapy efficacy in female mice.