Therapies that activate the host immune system have shown tremendous promise for a wide variety of solid tumors. However, in most cancer types, fewer than half of patients respond to these therapies. We have shown that epigenetic therapies can increase immune signaling from tumors, and sensitize them to immune therapy. Specifically, treatment with DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis) upregulate interferon signaling and T cell recruitment in solid tumors. Demethylation and expression of bidirectionally transcribed endogenous retroviruses (ERVs) is a major component of the dsRNA that activates this response. Treatment with a combination of DNMTI+ HDACi+ anti-PD-1 significantly reduces tumor burden and increases survival in a mouse ovarian cancer model. We thus define a major mechanism for how epigenetic regulation of noncoding RNA may induce cancer cells to increase attraction and activation of immune cells and sensitize patients to immunotherapy.