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Many forms of tumors are refractory to current therapies, including radiotherapy and chemotherapy targeting DNA damage response (DDR). Although DDR inhibitors, including PARP, ATM, and ATR inhibitors, have advanced in clinical trials, and are approved for treating other types of cancer, treatments targeting the DDR often encounter drug resistance when used as single agents, particularly in solid tumors. This drug resistance is caused by a metabolic rewiring that enables cancer cells to counteract a drug’s most damaging effects. Redox metabolism stands particularly as a prominent event in mechanisms of resistance. DNA repair genes and pathways are intrinsically involved in regulating bioenergetic metabolic pathways such as mitochondrial respiration, glycolysis, pentose phosphate pathway, and redox homeostasis. Many studies reported that tumor cells rely heavily on redox metabolism for survival upon genotoxic stress.  However, the molecular crosstalk between genomic instability and redox metabolism remains poorly understood. Understanding these signaling pathways will help elucidate how cancer cells exploit metabolic reprogramming in response to DNA damage, possibly harnessing redox vulnerabilities to overcome resistance to DDR inhibitors. Our research focuses on decoding the dialogue between genomic instability and redox homeostasis in cancer cells.