Domesticated retroelements contribute extensively as regulatory elements within host gene networks. Upon germline integration, retroelement mobilization is restricted through epigenetic silencing, mutational degradation, and innate immune defenses described as the viral mimicry response. Recent discoveries reveal how early events in tumorigenesis reactivate retroelements to facilitate onco-exaptation, replication stress, retrotransposition, mitotic errors, and sterile inflammation, which collectively disrupt genome integrity. The characterization of altered epigenetic homeostasis at retroelements in cancer cells also reveals new epigenetic targets whose inactivation can bolster responses to cancer therapies. Recent discoveries reviewed here frame reactivated retroelements as both drivers of tumorigenesis and therapy responses, where their reactivation by emerging epigenetic therapies can potentiate immune checkpoint blockade, cancer vaccines, and other standard therapies.

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