The Role of Mitochondrial ROS in Neoplastic Transformations, Progression and Therapeutic Targeting

Mitochondria are central regulators of cellular metabolism and survival and play a pivotal role in cancer development and progression through the production of reactive oxygen species (ROS), control of calcium homeostasis, regulation of autophagy, and modulation of cell death pathways. Mitochondria-derived ROS (mtROS) act as signaling mediators that influence tumor initiation, proliferation, metabolic reprogramming, metastasis, and therapeutic resistance by altering redox homeostasis, damaging mitochondrial DNA, and reshaping the tumor microenvironment. In addition to meeting the bioenergetic and biosynthetic requirements of rapidly proliferating cancer cells, mitochondrial metabolism modulates immune responses and supports cancer cell adaptation to hypoxia and nutrient deprivation. Accumulating evidence also highlights the dual role of mtROS, which can promote tumor progression at moderate levels yet trigger oxidative stress-induced cell death when excessively increased, making mitochondrial redox signaling an attractive therapeutic target. This review summarizes the major sources and regulation of mtROS, their involvement in cancer-associated signaling pathways, mitochondrial calcium dynamics, metabolic adaptations, and resistance to anticancer therapies, and discusses current and emerging mitochondrial-targeted strategies aimed at exploiting mtROS signaling to improve cancer treatment outcomes.