Shielded from Treatment: How Estrogen Fuels Sex-Biased Resistance to Cancer ADCs

Antibody-drug conjugates (ADCs) have emerged as a cornerstone of precision oncology; however, marked heterogeneity in clinical response remains a major hurdle, and the underlying biological determinants are still poorly understood.

Recently, researchers published a study in Cell titled "STING reprogramming by estrogen promotes neutrophil extracellular trap formation and sex-biased resistance to ADC therapy." Utilizing a "Phase II-like" preclinical trial across 55 patient-derived xenograft (PDX) humanized mouse models of CLDN18.2-positive pancreatic cancer, the team uncovered significant sex disparities in ADC therapeutic efficacy for the first time.

The study demonstrated that female hosts exhibit pronounced resistance to CLDN18.2-targeted ADCs. Mechanistically, this resistance is driven by estrogen-induced reprogramming of STING signaling, coupled with neutrophil extracellular trap (NET)–mediated "functional antigen shielding."

Biological sex serves as a pivotal determinant of tumor behavior and clinical outcomes. Mounting evidence indicates that sexual dimorphism—shaped by genetic, hormonal, immunological, and epigenetic factors—modulates cancer biology and therapeutic responsiveness. Sex-specific variations in efficacy and toxicity are already well documented in immune checkpoint blockade (ICB). Emerging clinical observations suggest that this phenomenon extends beyond ICB to other antibody-based targeted regimens.

For instance, subgroup analyses from the EV-301 trial revealed that the NECTIN-4-directed ADC enfortumab vedotin offered a more pronounced survival benefit in male patients than in female patients. Similarly, analyses of clinical trials in metastatic colorectal cancer (including PanaMa and FIRE-3) indicated that clinical benefit from anti-EGFR monoclonal antibodies was less consistent among female cohorts.

Because ongoing clinical trials evaluating CLDN18.2-targeted ADCs remain in early developmental stages and lack prespecified sex-stratified analyses, whether sex-related dimorphism governs response to CLDN18.2-ADC therapy had remained unclear.

To investigate this question, the researchers conducted a "Phase II-like preclinical trial" spanning 55 CLDN18.2-positive pancreatic cancer PDX models. Despite comparable target antigen expression between sexes, female models exhibited pronounced resistance to CLDN18.2-ADC therapy. Mechanistically, estrogen signals through G-protein coupled estrogen receptor 1 (GPER1) to upregulate TRAF6, redirecting tumor-intrinsic STING signaling away from IRF3-dependent interferon synthesis toward nuclear factor-κB (NF-κB) activation. This cascade triggers CXCL1 secretion, recruitment of neutrophils, and the formation of neutrophil extracellular traps (NETs).

Figure 1. Schematic diagram of the mechanism. (Yan J, et al., 2026)

These NETs form a dense, charged extracellular meshwork that physically impedes antibody accessibility to tumor-surface antigens—a phenomenon termed "functional antigen shielding"—thereby attenuating ADC cytotoxicity independent of antigen density. High NET burden also correlated with inferior therapeutic responses in three independent clinical cohorts treated with trastuzumab, cetuximab, or enfortumab vedotin. Pharmacological degradation of NETs using sivelestat restored ADC efficacy in female mice.

Collectively, these findings uncover an estrogen-driven mechanism of therapeutic resistance, offering broad implications for optimizing antibody-based therapeutics across oncology.