The relapse of breast cancer patients following anti-HER2 antibody therapies such as trastuzumab has been associated with residual disease progression due to resistance to therapy. We identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a crucial immune cascade of anti-HER2 trastuzumab responses in HER2+ breast cancer. Down-regulation of immune-regulated genes (IRG) signature is specifically associated with poor clinical outcomes of HER2+, but not other breast cancer subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of our in-house histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication through increased CD8+ T cells infiltration and long-term T cell memory in a HER2+ breast cancer mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2+ breast cancer to confer resistance to trastuzumab treatment.