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Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we perform multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing along with spatial profiling. We recover tumor microenvironmental features previously described to associate with therapy response. We subsequently identify five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which are associated with differential epigenetic plasticity and clinical outcomes, and for which we infer candidate transcription factor regulons. Furthermore, we reveal diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predict their significant interactions with microenvironmental cell types. We validate our findings in three external single-cell RNA sequencing (RNA-seq) and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.