Mitochondria-mediated tumor drug resistance: From mechanism insights to therapeutic strategies.

Drug resistance remains a major barrier to durable responses to chemotherapy, targeted therapy, radiotherapy, and immunotherapy. Mitochondria, once viewed mainly as bioenergetic organelles, are now recognized as adaptive signaling hubs that shape tumor survival under therapeutic pressure. Here, we review how mitochondrial dynamics, metabolic plasticity, redox remodeling, programmed cell death regulation, epithelial-mesenchymal transition, and intercellular mitochondrial transfer collectively drive tumor drug resistance. We highlight that resistant cancer cells exploit mitochondrial flexibility to switch between glycolysis and oxidative phosphorylation, reinforce antioxidant defenses, suppress apoptosis, ferroptosis, and cuproptosis, and remodel the tumor microenvironment through metabolic and immune crosstalk. We further discuss emerging therapeutic strategies targeting mitochondrial vulnerabilities, including OXPHOS inhibition, fusion-fission modulation, redox intervention, BH3 mimetics, ferroptosis/cuproptosis induction, and mitochondria-directed delivery systems. Finally, we propose a mechanism-guided translational framework to advance mitochondria-targeted therapies toward biomarker-driven precision oncology. This integrated perspective may help move mitochondria-targeted therapy from a broad preclinical concept toward biomarker-guided precision strategies for overcoming tumor drug resistance.