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

Estrogen-driven activation of STING signaling causes sex-biased resistance to antibody-drug conjugates in pancreatic cancer, reducing therapy effectiveness by up to 50%.

• Why it matters: Understanding sex differences in cancer therapy response is crucial, as females show significant resistance despite similar antigen levels, highlighting a gap in personalized treatment strategies.
• What they did: Researchers used 55 patient-derived xenografts and identified estrogen signaling via GPER1 upregulates TRAF6, shifting STING activity from interferon production to NF-κB activation, leading to NET formation that shields tumor antigens.
• The result: Disrupting NETs with sivelestat improved ADC responses in female mice, suggesting targeting NETs could enhance antibody therapy efficacy across sexes and various cancer types.