Combining the past and present to advance immuno-radiotherapy of cancer

Since its first clinical application, 120 years ago, radiotherapy evolved into a major anti-cancer treatment modality, offering high cure rates in many human malignancies. During the past ten years, the establishment of immune checkpoint inhibitors (ICIs) in cancer therapeutics has vigorously reintroduced the immune system's role in the outcome of radiotherapy and, conversely, the role of radio-vaccination in the efficacy of immunotherapy. The knowledge and clinical experience that founded the current era of immuno-radiotherapy started alongside with the birth of radiotherapy, and evolved through exhaustive experimental work, clinical trials on active specific immunotherapy, frustrating attempts to validate the importance of cytokine administration with radiotherapy, and, finally, the encouraging ICI-based clinical trials that opened the door to a far more encouraging perspective; radio-vaccination, through its old and new methods, is rising as a research field that promises to cure, previously incurable, disease. In this critical review, we focus on the scientific knowledge gathered through more than a century of research on radiotherapy interactions with the immune system. Understanding the origins of this promising therapeutic approach will substantially contribute to developing new immuno-radiotherapy policies in the fight against cancer.