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Summary: Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me3 in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant disease. : Hirukawa et al. link Trastuzumab resistance in ErbB2+ breast cancers with activity of the methyltransferase EZH2, a key epigenetic regulator. By silencing retrotransposons, EZH2 suppresses type-I interferon signaling to limit immune surveillance. Retrotransposon de-repression following EZH2 inhibition triggers interferon responses and sensitizes immunocompetent in vivo models to ErbB2 antibody therapy. Keywords: ErbB2/HER2, breast cancer, Polycomb Repressor Complex 2, PRC2, epigenetics, Trastuzumab resistance, endogenous retroviruses, immune surveillance, type I interferon signaling, transcriptional silencing