The DNA damage response in immunotherapy and radiation

PURPOSE: Deficiencies in DNA damage repair (DDR) and response represent a common alteration in tumors, and exploitation of this feature using therapeutics has become more prominent. METHODS AND MATERIALS: Recent work has highlighted the important interaction between DDR defects, as well as DDR targeting agents such as radiation and the immunogenicity of the tumor. This relationship emphasizes the potential for combination therapeutics with immune checkpoint inhibitors (ICI). Somatic mutations and DDR defects are some of the strongest predictors of response to ICI. RESULTS: This review highlights the interplay among DDR pathways, ionizing radiation, and ICI efficacy. The mechanisms of radiation immunogenicity, including the cytosolic DNA sensing cGAS/STING pathways, are also described. CONCLUSIONS: A greater mechanistic understanding of the complex interaction between the DNA damage response and the immune system will expand the therapeutic potential of immunotherapy for patients with advanced cancer.