Research progress of DNA damage repair (DDR) and DDR inhibitors in tumor immunotherapy

Abstract

Human cells possess a complex network of regulatory systems——the DNA damage repair pathway (DDR), to deal with various DNA damage to prevent the inheritance of deleterious mutations. DDR perform its functions via cell cycle checkpoint activation. Mutations in the DDR gene are also the basis for tumor progression, metastasis, and therapeutic effect to treatments that cause DNA damage. Consequently, DDR has received high attention for its role in the therapy against cancer, and the related experiments have been carried out to further explore. Up to now, PARP inhibitors such as Olaparib, Rucaparib, Niraparib, Talazoparib, etc. have been approved for marketing and clinical use, other DDR inhibitors (DDRi) such as ATMi/ATRi/DNA-PKi, Chk1/2i, and WEE1i have partially entered clinical trials. Synthetic lethality has led to the exploration of combination of DDRi with other anti-tumor therapies, in particular, the combination of DDRi with immunotherapies such as chemoradiotherapy and immune checkpoint inhibitors (ICIs) has achieved potential efficacy. This article reviewed the DDR inhibitors that are currently in development or in clinical therapy, analyzed the limitations and future development prospects, and stated the mechanisms and clinical trials in antitumor and immunotherapy, to provide ideas for the subsequent development of DDRi and enhance the efficacy of antitumor immunotherapy.