Radiotherapy (RT) affects anti-tumor immunity. However, the exact impact of RT on anti-tumor immune response differs among cancer types, RT dose and fractions, patients’ innate immunity, and many other factors. There are conflicting findings on the optimal radiation dose and fractions to stimulate effective anti-tumor immunity. High-dose radiotherapy (HDRT) acts in the same way as a double-edged sword in stimulating anti-tumor immunity, while low-dose radiotherapy (LDRT) seems to play a vital role in modulating the tumor immune microenvironment. Recent preclinical data suggest that a ‘hybrid’ radiotherapy regimen, which refers to combining HDRT with LDRT, can reap the advantages of both. Clinical data have also indicated a promising potential. However, there are still questions to be addressed in order to put this novel combination therapy into clinical practice. For example, the selection of treatment site, treatment volume, the sequencing of high-dose radiotherapy and low-dose radiotherapy, combined immunotherapy, and so on. This review summarizes the current evidence supporting the use of HDRT + LDRT, explains possible immune biology mechanisms of this ‘hybrid’ radiotherapy, raises questions to be considered when working out individualized treatment plans, and lists possible avenues to increase efficiency in stimulating anti-tumor immunity using high-dose plus low-dose radiotherapy.