A rise in double-strand breaks sensitizes tumors to oxidative metabolism inhibitors

Double-strand breaks (DSBs) accumulate in tumoral DNA due to deficiencies in homologous recombination (HR) repair, such as mutations in BRCA genes, or following antitumoral treatments. In the present study, we show that DSB accumulation, irrespective of origin, triggers an adaptive shift toward oxidative metabolism. We demonstrate that DSBs downregulate the glycolytic transcription factor HIF-1α. This downregulation reduces PDHK1 expression, thereby activating the pyruvate dehydrogenase complex, a key mitochondrial gatekeeper of cellular metabolism. We establish that the induction of oxidative metabolism represents a therapeutically actionable vulnerability across diverse cancer types, independent of HR proficiency. Targeting this metabolic switch in combination with DSB-inducing chemotherapies synergizes in vivo, resulting in significantly reduced tumor growth. Collectively, our findings reveal a critical feedback loop linking DSBs to cancer cell metabolism that constrains metabolic plasticity and creates a compelling therapeutic opportunity for rational combination strategies.