Targeting DNA Methylation Reactivates Type I Interferon Signalling in Bone-Metastatic Breast Cancer

Bone metastasis remains a major clinical challenge in advanced breast cancer. Downregulation of type I interferon signalling, a critical immunomodulatory pathway in anti-cancer immunity and disease progression, is a defining feature of this process. Here, we utilised an IFN-reporter system to perform unbiased epigenetic compound screens to identify agents that could restore type I IFN signalling. This screen identified Decitabine, a DNA hypomethylating agent, that enhanced tumor immunogenicity across a broad range of mouse and human breast cancer cell lines, including bone-derived lines. Mechanistically, suppression of interferon-stimulated genes is highly correlated with elevated DNMT1 expression in bone metastasis compared with primary tumor, in both mouse models and matched human samples. Decitabine treatment was sufficient to reactivate interferon stimulated genes in bone-derived 4T1.2 cell lines via hypomethylation of type I interferon pathway gene promoter regions. Correspondingly, in the syngeneic 4T1.2 metastasis mouse model, Decitabine treatment conferred a survival benefit and reduced metastatic potential, particularly in bone. Our findings reveal DNA methylation as a key regulator of the transcriptional programs underlying bone metastasis, providing mechanistic insight into how Decitabine reactivates type I interferon signalling and reduces metastatic potential, highlighting epigenetic reprogramming as a promising approach for targeting metastatic breast cancer.