Intercellular mitochondrial exchange shapes tumor evolution, microenvironment adaptation, and therapeutic vulnerabilities

Mitochondrial transfer has emerged as a previously underappreciated mode of intercellular communication with major implications for tumor biology. Beyond their cell-autonomous roles in bioenergetics and signalling, mitochondria can be exchanged between cells as intact organelles or as mitochondrial cargo, thereby reshaping the metabolic state, stress tolerance and therapy responsiveness of recipient cells. In tumors, mitochondrial transfer can buffer oxidative stress, compensate for mtDNA damage and restore oxidative phosphorylation, enabling metabolic plasticity and contributing to immune dysfunction within the tumor microenvironment. This review synthesized current evidence for the structural routes and regulatory logic of mitochondrial exchange in cancer, spanning actin-based tunneling nanotubes, extracellular vesicle-mediated export and uptake, and other contact-dependent mechanisms. We highlight actionable "gatekeepers" that constrain transfer efficiency, including conduit biogenesis programs, MIRO1/2-TRAK-motor coupling that licenses mitochondrial trafficking, and EV biogenesis/uptake modules, as well as microenvironmental triggers such as hypoxia and redox stress. We also evaluate emerging methodological standards required to distinguish bona fide organelle transfer from dye leakage or indirect cargo exchange, and discuss how orthogonal validation (genetic reporters, mtDNA barcoding and functional rescue assays) can improve rigor and comparability across studies. By integrating current findings, this article aims to provide a theoretical foundation and strategic guidance for targeting tumor metabolic regulation and improving precision oncology approaches.