对 HER2 靶向治疗的耐药性是 HER2 乳腺癌 (BC) 患者治疗失败的主要原因。鉴于免疫微环境在肿瘤发展中的关键作用，目前缺乏充分考虑免疫浸润的理想预后模型。在本研究中，进行 WGCNA 分析以发现免疫相关信号传导与 HER2 BC 预后之间的关系。赫赛汀耐药 BC 细胞系建立后，对耐药细胞系的转录谱和 GSE76360 队列的 RNA 测序数据进行了分析，以寻找候选基因。通过 Cox 回归、XGBoost 和 Lasso 算法对 TCGA 数据库中的 85 个 HER2 BC 样本进行分析，以概括出可信的免疫相关预后指数 (IRPI)。通过多种算法进一步分析 IRPI 特征与肿瘤微环境之间的相关性，包括单细胞 RNA 测序数据分析。 IRPI高的患者肿瘤免疫微环境受到抑制，预后较差。 IRPI 表明赫赛汀耐药 HER2 BC 中 I 型干扰素信号传导的抑制得到了验证。我们阐明了 cGAS-STING 通路的抑制是具有高 IRPI 的赫赛汀耐药 BC 免疫逃逸的关键决定因素。 STING 激动剂和 DS-8201 的组合可以作为赫赛汀耐药 HER2 BC 的新策略。© 作者。

Resistance to HER2-targeted therapy is the major cause of treatment failure in patients with HER2+ breast cancer (BC). Given the key role of immune microenvironment in tumor development, there is a lack of an ideal prognostic model that fully accounts for immune infiltration. In this study, WGCNA analysis was performed to discover the relationship between immune-related signaling and prognosis of HER2+ BC. After Herceptin-resistant BC cell lines established, transcriptional profiles of resistant cell line and RNA-sequencing data from GSE76360 cohort were analyzed for candidate genes. 85 samples of HER2+ BC from TCGA database were analyzed by the Cox regression, XGBoost and Lasso algorithm to generalize a credible immune-related prognostic index (IRPI). Correlations between the IRPI signature and tumor microenvironment were further analyzed by multiple algorithms, including single-cell RNA sequencing data analysis. Patients with high IRPI had suppressive tumor immune microenvironment and worse prognosis. The suppression of type I interferon signaling indicated by the IRPI in Herceptin-resistant HER2+ BC was validated. And we elucidated that the suppression of cGAS-STING pathway is the key determinant underlying immune escape in Herceptin-resistant BC with high IRPI. A combination of STING agonist and DS-8201 could serve as a new strategy for Herceptin-resistant HER2+ BC.© The author(s).