Esophageal adenocarcinoma (EAC) is an extremely aggressive disease with an overall 5 years survival rate of less than 20%. Current treatments, such as surgery, or chemo- and radiotherapy have only little effect on survival. Attempts to combine these treatment modalities were only limited successful with marginal improvement of prognosis. Therefore, novel treatment strategies are urgently needed. In a previous study we demonstrated that dendritic cell (DC) immunotherapy may be an attractive and promising approach to treat EAC. Although potent immune responses can be raised by DC therapy, there are several concerns about the immunosuppressive microenvironment that characterizes these cancers, which may inhibit an effective immune response. Here a general overview is given of the current management of EAC and immunotherapies. More specific focus is on the EAC tumor microenvironment, and several potential combinatorial strategies that can be explored for improving treatment of EAC.