ABSTRACT
Radiotherapy (RT), unlike chemotherapy, is one of the most routinely used and effective genotoxic and immune response inducing cancer therapies with an advantage of reduced side effects. However, cancer can relapse after RT owing to multiple factors, including acquired tumor resistance, immune suppressive microenvironment buildup, increased DNA repair, thus favoring tumor metastasis. Efforts to mitigate these undesirable effects have drawn interest in combining RT with immunotherapy, particularly the use of immune checkpoint inhibitors, to tilt the pre-existing tumor stromal microenvironment into long-lasting therapy-induced antitumor immunity at multiple metastatic sites (abscopal effects). This multimodal therapeutic strategy can alleviate the increased T cell priming and decrease tumor growth and metastasis, thus emerging as a significant approach to sustain as long-term antitumor immunity. To understand more about this synergism, a detailed cellular mechanism underlying the dynamic interaction between tumor and immune cells within the irradiated tumor microenvironment needs to be explored. Hence, in the present review, we have attempted to evaluate various RT-inducible immune factors, which can be targeted by immunotherapy and provide detailed explanation to optimally maximize their synergy with immunotherapy for long-lasting antitumor immunity. Moreover, we have critically assessed various combinatorial approaches along with their challenges and described strategies to modify them in addition to providing approaches for optimal synergistic effects of the combination.