%0 Journal Article
%T A High Immune-Related Index with the Suppression of cGAS-STING Pathway is a Key Determinant to Herceptin Resistance in HER2+ Breast Cancer.
%A Cai R
%A Chen Q
%A Zhao D
%A Wang Y
%A Zhou L
%A Zhang K
%A Shan J
%A Li Z
%A Chen Y
%A Zhang H
%A Feng G
%A Zhu X
%A Deng R
%A Tang J
%J Int J Biol Sci
%V 20
%N 9
%D 2024
%M 38993569
%F 10.75
%R 10.7150/ijbs.94868
%X 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.