文章 :

p95HER2（HER2癌蛋白的截短形式）可驱动HER2阳性乳腺癌中的免疫抑制程序，从而限制曲妥珠单抗德鲁替康的疗效。

p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2+ breast cancer that limits trastuzumab deruxtecan efficacy

原文发布日期：2025-06-27

英文摘要：

Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies and immuno-oncology agents poses a major challenge in treating HER2-positive breast cancer. Here we demonstrate that p95HER2, a truncated form of HER2, drives immune evasion in HER2-positive female breast cancer, enhancing tumor growth and conferring therapy resistance. This stems from the unique ability of p95HER2 to promote cancer cell-intrinsic programmed death ligand 1 expression and secretion of immunosuppressive mediators including interleukin 6. In preclinical models, this impairs the efficacy of trastuzumab deruxtecan, a HER2-directed antibody–drug conjugate (ADC) that relies on immunogenic responses to cell death for full efficacy. Importantly, we find that neratinib potently directs proteasomal degradation of p95HER2, relieving its immunosuppressive effects, and provide proof of concept that neratinib and/or agents targeting p95HER2 downstream mediators can restore antitumor immunity and trastuzumab deruxtecan efficacy. This study reveals a p95HER2-specific therapy resistance mechanism in HER2-positive female breast cancer and highlights the potential value of targeting p95HER2 to improve outcomes with ADCs or immuno-oncology agents.

摘要翻译：

针对人类表皮生长因子受体2（HER2）靶向治疗和免疫肿瘤药物的耐药性，是当前HER2阳性乳腺癌治疗面临的主要挑战。本研究首次证实，HER2的截短形式p95HER2能驱动HER2阳性女性乳腺癌的免疫逃逸，促进肿瘤生长并导致治疗抵抗。其机制源于p95HER2具有独特的能力：既可促进癌细胞本征性程序性死亡配体1的表达，又能分泌包括白细胞介素6在内的免疫抑制介质。临床前模型显示，这一特性会削弱抗体偶联药物（ADC）德曲妥珠单抗的疗效——该药物的完全有效性依赖于细胞死亡引发的免疫原性反应。值得注意的是，我们发现来那替尼能有效引导蛋白酶体降解p95HER2，从而解除其免疫抑制作用，并通过概念验证表明：来那替尼和/或靶向p95HER2下游介质的药物可恢复抗肿瘤免疫力及德曲妥珠单抗疗效。本研究不仅揭示了HER2阳性女性乳腺癌中p95HER2特异的治疗抵抗机制，更凸显了靶向p95HER2对于改善ADC或免疫肿瘤药物临床疗效的潜在价值。

原文链接:

 https://www.nature.com/articles/s43018-025-00969-4