Esophageal cancer is still the worst malignant disease, and its prognosis is still poor. To improve the outcome of esophageal cancer, a novel therapy is needed. Here, we demonstrate some novel therapeutic modalities. 1) Immunotherapy: We developed a novel immunotherapy using both intratumoral administration of dendritic cell and radiation for esophageal squamous cell carcinoma. By using radiation, abscopal effect can be induced and this phenomenon enhances immune-reaction and anti-tumor effect mediated by T-cell reaction. A phase I clinical trial is now progressing. 2) New drugs: We have tested some drugs whether some drugs can enhance antitumor effect. From the results of our research, we found that COX2-inhibitor has a capacity to enhance antitumor effect of 5-FU, cisplatin or radiation. On the other hand, newly developed HDAC-inhibitor strongly suppressed tumor growth. HDAC-i modifies epigenetic structure and elucidates anti-tumor effect. 3) MicroRNA: We found that some microRNAs have an anti-tumor effect. For example, we found that miR-145, miR-133a and miR-133b are tumorsuppressive miRNA which targets FSCN1 in esophageal squamous cell carcinoma. Additionally, miR-203 can inhibit migration and invasion activity by regulating LASP1. 4) A newly developed nano-particle: We developed nano-particle which consisted of liposome and ICG. Nano-particles are accumulated in the tumors by EPR effect (Enhanced permeation and retention effect). Using this effect we successfully developed a combination therapy using ICG-liposome and near infrared radiation. 5) Modulated electro-hyperthermia (mEHT): The 13.56 MHz radio frequency was used for mEHT. MEHT can induce apoptosis and suppress tumor growth. This anti-tumor effect is tumor specific and the mechanism is explained by Warburg effect, Szentgyorgyi effect and Fractal effect. We further developed a combination therapy of dendritic cells and mEHT. A phase I study of mEHT for esophageal cancer is now progressing. From these translational approaches, we have been developing novel therapeutic modalities to improve the outcome of esophageal squamous cell carcinoma.