Using triple radio-immunotherapy to overcome cancer immunotherapy resistance

Cancer is a widespread public health issue and has become a leading cause of death in most countries. In recent decades, immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has altered the clinical practice of cancer treatment and evolved into a first-line clinical strategy. ICIs significantly improve clinical outcomes and provide long-term benefits. However, several barriers limit the efficacy of cancer immunotherapy. First, ICIs as a monotherapy have limited effects, and only a minority of patients experience durable survival benefits. Second, a proportion of patients who initially show favorable responses gradually develop acquired resistance. Finally, current ICIs are directed primarily to therapy naive patients, and alterations in the immune microenvironment after treatment are not considered. Therefore, existing ICIs might be not the most suitable therapy for patients who have received prior treatments. In addition, these ICIs might not satisfy the requirement for personalized therapies. To address these barriers, researchers have extensively investigated combination treatment strategies. Preclinical and clinical data have shown that radiotherapy plus immuno therapy is an effective combination strategy to improve systemic antitumor response by amplifying the immunomodulatory effects. Many attempts have been made to combine radiotherapy with immunotherapy. Herrera and colleagues1 have found that a model named "RACIM" comprising low-dose radiotherapy plus immunotherapy has synergistic effects on tumor killing in patients with poor immune infiltration. Our team have conducted a more in-depth study of radiotherapy combined with ICIs (iRT), given that novel radiotherapy modalities, such as low dose irradiation (LDIR) and alternative immune targets, may provide a triple radio-immunotherapy that more powerfully increases treatment efficacy.