Cell repopulation, rewiring metabolism, and immune regulation in cancer radiotherapy

Abstract Cancer radiotherapy (RT) demonstrates the benefit of local control with fewer side-effects compared to chemotherapy. To further improve the overall efficacy of RT and RT-combined therapies, studies revealing the mechanisms involved in tumor response to radiation are required. Accumulating new evidence has demonstrated that the microenvironment of solid tumors, such as cancers in lung, breast, and liver, holds a highly heterogenic population of tumor cells, an array of stromal cells with different functions, as well as non-cellular components. The observed tumor responses to cancer radiotherapy are pooled signals generated from the heterogenic cell populations such as the survival of radioresistant tumor cells and the infiltrated immune cells. Thus, further elucidation of key dynamics in irradiated tumor microenvironment (ITME), including repopulation of cancer stem cells, metabolic shifting, and radiation-induced tumor immunogenicity, will be necessary to significantly enhance the outcome of RT or RT-combined immunotherapy. This review summarizes the current experimental and clinical results of these three dynamics in ITME.