In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU-thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio-sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno-modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues.