Emerging roles of mitochondria in cancer biology: mechanisms and therapeutic targeting

Abstract Cancer remains a leading cause of global mortality, with increasing incidence and limited therapeutic options for advanced-stage disease. Accumulating evidence indicates that mitochondrial reprogramming is a key regulator of cancer biology, coordinating energy metabolism, oxidative stress, epigenetic remodeling, and immune evasion to shape the tumor microenvironment (TME) and cancer cell fate. Dysregulated mitochondrial dynamics, mitochondrial DNA (mtDNA) alterations, and metabolite-mediated signaling sustain proliferative capacity, angiogenesis, and phenotypic plasticity, thereby promoting tumor progression. Translational research has further identified mitochondrial features as prognostic biomarkers. Several therapeutic strategies targeting mitochondrial metabolism, including inhibitors of respiratory complex I and glutamine metabolism, have reached clinical evaluation, while mutant isocitrate dehydrogenase (IDH) inhibitors have progressed further, with several agents receiving regulatory approval. In contrast, therapeutic approaches that directly target mitochondrial dynamics, such as fission and fusion machinery, remain largely at the preclinical stage. In this review, we summarize the mechanistic and clinical evidence supporting the roles of mitochondria in cancer and discuss emerging therapeutic strategies targeting mitochondrial vulnerabilities, including rational combinations with chemotherapy, radiotherapy, and targeted therapies, as potential approaches for precision oncology.