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. Epigenetic therapy can increase immune signaling from tumors, sensitizing to immune therapy in mouse models of cancer. DNA methyltransferase inhibitors (DNMTis) upregulate interferon signaling in solid tumors by cytosolic sensing of double-stranded RNA (dsRNA), triggering a Type I Interferon response and apoptosis. Demethylation and expression of bidirectionally transcribed endogenous retroviruses (ERVs) is a major component of the dsRNA that activates the response. Adding histone deacetylase inhibitors (HDACis) to DNMTis can augment this upregulation. In mouse models of cancer, DNMTi stimulate the interferon response through ERV upregulation, leading to increased recruitment of T cells, including tumor-killing T Effector (CD3+CD8+) cells, to the tumor. This epigenetic therapy causes increased activation of CD8 T cells and natural killer cells, an increase in helper T cells, and a reduction in suppressive myeloid cells. Both the immune cell activation and the tumor burden decrease by DNMTi are dependent on activation of the Type I Interferon response and are associated with an increase in transcription of mouse ERVs. Treatment of this mouse model with the above drug combination plus anti-PD-1 significantly reduces tumor burden and increases survival. Separately, EZH2 inhibitors can increase signaling from tumor cells to recruit immune cells to kill tumors. Lastly, DNMTis can directly affect methylation on T cells to reverse T cell exhaustion. This presentation will cover work from our group and others on the use of epigenetic therapies to reverse immune evasion in cancers.