Tumor Microenvironment of Esophageal Cancer

Simple Summary Esophageal cancer is one of the top ten most deadly cancers. Even when diagnosed in a curable stage, patients prognosis poor. One of the parameters that is very relevant for long-term survival is response to radio(chemo)therapy prior surgery. Complete response rates are between 24 and 50 percent. This puts more than a half of every esophageal cancer patient that is diagnosed in a non-metastasized stage at high risk of recurrence. To improve response rates of treatment regimens prior curative surgery is, therefore, a major challenge in treating esophageal cancer. Not only the response of the cancer cell itself to cancer therapy is determining patients’ fate. Cells around the tumor cells called the tumor microenvironment that together with the cancer cell constitute a malignant tumor are also involved in tumor progression and therapy response. This review depicts the most important parts of the esophageal cancer microenvironment, evaluates chances and challenges of current already established therapeutic concepts that target this microenvironment. It furthermore elucidates specific pathways that are potential valuable targets in the future. Abstract Esophageal cancer is among the top ten most deadly cancers worldwide with adenocarcinomas of the esophagus showing increasing incidences over the last years. The prognosis is determined by tumor stage at diagnosis and in locally advanced stages by response to (radio-)chemotherapy followed by radical surgery. Less than a third of patients with esophageal adenocarcinomas completely respond to neoadjuvant therapies which urgently asks for further strategies to improve these rates. Aiming at the tumor microenvironment with novel targeted therapies can be one strategy to achieve this goal. This review connects experimental, translational, and clinical findings on each component of the esophageal cancer tumor microenvironment involving tumor angiogenesis, tumor-infiltrating immune cells, such as macrophages, T-cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts. The review evaluates the current state of already approved concepts and depicts novel potentially targetable pathways related to esophageal cancer tumor microenvironment.