2026年10月6日，天津医科大学郝继辉等科学家在《细胞》发表研究，揭示了雌激素重编程STING促进中性粒细胞胞外陷阱形成，导致ADC治疗的性别偏倚耐药。

癌症治疗反应中的性别差异仍知之甚少。研究人员利用一项针对55例CLDN18.2+胰腺癌患者来源异种移植物的“II期样临床前试验”，发现尽管抗原表达相当，雌性对CLDN18.2靶向抗体-药物偶联物（ADC）治疗表现出明显的偏倚耐药。机制上，雌激素通过GPER1信号上调TRAF6，将肿瘤内在STING信号从IRF3介导的干扰素产生重定向至核因子κB（NF-κB）激活。这驱动CXCL1分泌、中性粒细胞募集和中性粒细胞胞外陷阱（NET）形成。NET形成带电的细胞外网络，限制抗体进入肿瘤细胞表面抗原——研究人员将这一机制称为功能性抗原屏蔽——从而在不依赖抗原表达的情况下降低ADC细胞毒性。NET负荷还与三个临床队列中对曲妥珠单抗、西妥昔单抗和恩弗妥单抗维多汀的较差反应相关。使用西维来司他进行药理学NET破坏恢复了雌性小鼠中的ADC疗效。这些发现揭示了一种雌激素驱动的耐药机制，对基于抗体的癌症治疗具有广泛意义。

附：英文原文

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

Author: Jingrui Yan, Tianxing Zhou, Shangheng Shi, Guohua Mao, Jingbo Xu, Yu Zhang, Yaqi Zhang, Huizhi Sun, Yifei Wang, Xiuchao Wang, Chongbiao Huang, Rui Liu, Deqing Hu, Shengyu Yang, Jun Yu, Yukuan Feng, Yongjie Xie, Bin Wang, Jihui Hao

Issue&Volume: 2026-10-06

Abstract: Sex differences in cancer therapy response remain poorly understood. Using a “phase II-like preclinical trial” across 55 CLDN18.2+ pancreatic cancer patient-derived xenografts, we identify marked female-biased resistance to CLDN18.2-targeted antibody-drug conjugate (ADC) therapy despite equivalent antigen expression. Mechanistically, estrogen signals through GPER1 to upregulate TRAF6, redirecting tumor-intrinsic STING signaling from IRF3-mediated interferon production toward nuclear factor κB (NF-κB) activation. This drives CXCL1 secretion, neutrophil recruitment, and neutrophil extracellular trap (NET) formation. NETs form a charged extracellular network that restricts antibody access to tumor-cell-surface antigens—a mechanism we term functional antigen shielding—reducing ADC cytotoxicity independently of antigen expression. The NET burden also correlated with poorer responses to trastuzumab, cetuximab, and enfortumab vedotin across three clinical cohorts. Pharmacologic NET disruption with sivelestat restored ADC efficacy in female mice. These findings reveal an estrogen-driven resistance mechanism with broad implications for antibody-based cancer therapy.

DOI: 10.1016/j.cell.2026.09.031

Source: https://www.cell.com/cell/abstract/S0092-8674(26)01133-5