Intercellular Mitochondrial Trafficking as a Master Regulator of Tumor Progression and Cancer Stem Cell Plasticity

Intercellular mitochondrial trafficking has emerged as an important mechanism influencing tumor progression, metabolic adaptability, and cancer cell plasticity. Beyond their classical bioenergetic functions, mitochondria act as central regulators of redox homeostasis, signalling pathways, and epigenetic remodelling. Increasing evidences suggest that mitochondria can be transferred between tumor, stromal, and immune cells through tunnelling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and cell fusion within the tumor microenvironment. This dynamic exchange enables metabolically compromised cancer cells to restore oxidative phosphorylation, optimize energy production, and survive under hypoxia and therapeutic stress. Mitochondrial transfer has been increasingly associated with enhanced cellular plasticity and adaptive phenotypic transitions, including the acquisition of stem-like features that contribute to tumor heterogeneity, metastasis, and treatment resistance. In addition to bioenergetic restoration, transferred mitochondrial DNA and metabolites participate in retrograde signalling, linking metabolic state to epigenetic regulation and transcriptional reprogramming. This metabolic epigenetic interplay supports tumor cell adaptation to environmental stress and therapeutic pressure. Although significant progress has been made, the precise mechanisms governing mitochondrial integration and their long-term impact on cellular phenotypes remain incompletely understood. A deeper understanding of these processes may reveal new therapeutic strategies to disrupt tumor adaptability and improve treatment outcomes.