Translational Aspects of DNA Damage Repair in Optimizing Cancer Chemotherapy

The DNA Damage Repair (DDR) signaling pathway serves as a crucial molecular hub that regulates chemotherapy efficacy, offering significant translational value in the field of precision oncology. This review systematically analyzes the molecular mechanisms of five core DDR pathways (Homologous Recombination Repair, Non-Homologous End Joining, Base Excision Repair, Nucleotide Excision Repair, and Mismatch Repair) in mediating chemotherapy resistance in tumors, and thoroughly elucidates the correlation between key molecular events-such as BRCA1/2 deficiency, MMR functional abnormalities, and Ataxia Telangiectasia Mutated/Ataxia Telangiectasia and Rad3-related (ATM/ATR) signaling pathway dysregulation-and chemotherapy sensitivity. The DDR deficiency biomarker system established through the integration of multi-omics data provides molecular classification tools for predicting the efficacy of platinum-based drugs. This study focuses on the mechanism by which Poly ADP-Ribose Polymerase inhibitors reverse Homologous Recombination-Deficient tumor resistance through "synthetic lethality" effects while also revealing the synergistic anti-tumor effects of ATM/ATR inhibitors in combination with chemotherapeutic agents. The research presents an innovative molecular synergy model between DDR regulation and Immune Checkpoint Blockade, confirming that tumor neoantigen release induced by DDR deficiency can enhance immunotherapy responses. This article also provides perspectives on multidimensional intervention strategies based on the DDR network, including the development of inhibitors targeting novel DDR targets, the establishment of DDR pathway functional assessment systems based on multidimensional biomarkers, and the investigation of synergistic paradigms between DDR and novel therapeutic modalities. Additionally, we explore the dynamic evolution mechanisms of DDR-mediated chemotherapy resistance by analyzing the interactions between DDR and metabolic reprogramming, as well as other related processes. These breakthrough advances provide theoretical foundations and innovative directions for overcoming chemotherapy resistance and advancing personalized treatment, marking a new era in cancer therapy characterized by precision targeting of DDR pathways.