Esophageal cancer is a disease characterized by a substantial genomic- and immunological heterogeneity and dismal treatment outcomes. In this thesis, several molecular and immunological factors influencing the treatment outcome of patients with localized esophageal cancer were identified, with a key role for T cell mediated immunity and a type I interferon response. Treatment outcomes of localized esophageal cancer might be further improved by comprehensive upfront tumor microenvironment analysis and selection of patients with immunosuppressive traits for immunomodulation before chemoradiotherapy.