Therapeutic Targeting of DNA Damage Repair in the Era of Precision Oncology and Immune Checkpoint Inhibitors

Cancer manifestation is a multistep process involving accumulation of various genetic and epigenetic changes that results in oncogenic ‘‘hallmarks of cancer’’ processes including genomic instability. Exploitation of aberrant DNA-damage response (DDR) mechanisms in cancer is in part a goal of many therapeutic strategies, and recent evidence supports the role of targeting DDR in modulating the tumor immune microenvironment to enhance immunotherapeutic response. Improved cancer profiling, including next-generation and whole-genome mutational sequencing of tumor tissue, as well as circulating nucleic acids, has enhanced our understanding of the genetic and epigenetic molecular mechanisms in tumorigenesis and will become fundamental to precisely target tumors and achieve cancer control. With the successes of poly(ADP-ribose) polymerase inhibitors (PARPi) and immunotherapies, the intersection of DDR molecular machinery and corresponding antitumor immune response has gained much interest with a focus on achieving therapeutic synergy using DNA damage-targeting agents and immunotherapy. In this review, we provide a bench-to-bedside overview of the fundamentals of DDR signaling and repair as they relate to cancer therapeutic strategies including novel DDR-targeting agents. We also discuss the underlying mechanisms that link DDR signaling to antitumor immunity and immunotherapy efficacy, and how this knowledge can be used to improve precision medicine approaches in the treatment of cancer.