Background: There is a critical need to develop effective therapeutic approaches for patients with esophageal cancer, a leading cause of cancer mortality. Recently, immune checkpoint blockade (ICB) has demonstrated modest survival benefit in gastroesophageal cancer patients. Epigenetic therapies, including DNA methyltransferases (DNMT) and histone deacetylases (HDACs), have shown to enhance tumor immune recognition by directly upregulating antigen presentation and by activation of type-1 interferon response triggered by cytoplasmic double-stranded RNA, a phenomenon known as viral mimicry. In other cancer models, epigenetic therapy has shown early promise by enhancing the effectiveness of ICB via addictive antiproliferative effects, enhanced immune activation and reversal of T cell exhaustion towards a memory-effector T-cell phenotypes. Methods: Esophagojejunostomy was performed to induce gastroduodenojejunal reflux in rats, leading to development of EAC. At 32 weeks postop, animals were randomized into eight treatment and control groups: placebo ± radiation, epigenetic treatment ± radiation, immunotherapy treatment ± radiation, and concurrent epigenetic and immunotherapy ± radiation. Animals underwent three 14 day cycles of epigenetic treatment or placebo. Each cycle consisted of one week of DNMT treatment or placebo at a dose of 0.5mg/kg, followed by one week of HDAC treatment or placebo at a dose of 2mg/kg. Animals received one 3mg/kg dose of PD1 inhibitor or placebo on day 12 of each cycle. Safety and efficacy were evaluated via objective health assessments, change in tumor volume, immunofluorescent labeling and RT-PCR. Results: Seventy of 74 randomized animals reached study end-point with no significant differences in mortality observed across groups (p = 0.556). There were no significant differences in observed health scores or weights between all groups (p = 0.431 and p = 0.882, respectively). Pre to posttreatment, mean MRI tumor volume increased by 263.1% and 90.9% in the placebo and the placebo plus radiation groups, respectively. The largest tumor reduction was observed in the concurrent treatment groups, 84.5% and 61.8% with and without radiation, respectively. Additionally, independent epigenetic and immunotherapy treatments with or without radiation also exhibited decrease in tumor volume, but to a lesser extent than the concurrent regimens (p = 0.005). Immunofluorescent labeling demonstrated a significant increase in CD3+ CD8+ T cells in all treatment groups compared to placebo (p = < 0.001). Gene expression displayed upregulation of CD206 (p = 0.002), TNFα (p = < 0.001), and Arg1 (p = < 0.001) in treatment arms compared to placebo. Conclusions: This study establishes addictive antitumor efficacy and enhanced immune sensitization for a concurrently sequenced treatment, combining epigenetic therapy and radiation with immunotherapy, to treat EAC.