Mitochondrial dysfunction and ROS signaling drive metabolic adaptation and plasticity in cancer

Mitochondrial dysfunction and reactive oxygen species (ROS) are increasingly recognized as key drivers of cancer metabolism, redox homeostasis, and cellular adaptation. Beyond their classical roles in energy production and oxidative balance, mitochondria function as central regulators of metabolic signaling influencing tumour growth, survival, and therapeutic response. Although mitochondrial dysfunction, redox imbalance, and metabolic adaptation have been extensively investigated, these interconnected processes are often examined independently, limiting a comprehensive understanding of their collective contribution to tumour progression. Emerging evidence demonstrates that mitochondrial dysfunction and ROS promote metabolic adaptation and plasticity, partly through epigenetic reprogramming, enabling cancer cells to survive and proliferate under conditions of energetic, environmental, and therapeutic stress. This review synthesizes current evidence linking mitochondrial dysfunction, ROS signaling, and metabolic adaptation, with particular emphasis on the molecular mechanisms underlying these interactions and their role in therapy resistance. It also discusses emerging therapeutic strategies targeting oxidative phosphorylation (OXPHOS), redox homeostasis, and metabolic adaptation, while highlighting the challenges posed by metabolic plasticity, tumour heterogeneity, and treatment-associated toxicities. Collectively, the evidence supports integrated therapeutic approaches that combine mitochondrial and metabolic targeting with biomarker-guided patient stratification to improve the durability and precision of cancer treatment.