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DNA-based vaccination is a promising approach to cancer immunotherapy. DNA-based vaccines specific for tumor-associated antigens (TAAs) are indeed relatively simple to produce, cost-efficient and well tolerated. However, the clinical efficacy of DNA-based vaccines for cancer therapy is considerably limited by central and peripheral tolerance. During the past decade, considerable efforts have been devoted to the development and characterization of novel DNA-based vaccines that would circumvent this obstacle. In this setting, particular attention has been dedicated to the route of administration, expression of modified TAAs, co-expression of immunostimulatory molecules, and co-delivery of immune checkpoint blockers. Here, we review preclinical and clinical progress on DNA-based vaccines for cancer therapy.