Emerging Roles of Extracellular Vesicle-Mediated Transfer of Mitochondrial and Mitochondrial Components in Cancer.

Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate the mechanisms governing the packaging of mitochondria and their constituents into EVs and subsequently highlight their multifaceted functions across various malignancies, including breast cancer, prostate cancer, blood malignancies, head and neck squamous cell carcinoma, digestive system cancers, etc. Mitochondrial cargo, such as intact mitochondria, mitochondrial DNA (mtDNA), and RNA (mtRNA), are shown to reconfigure metabolism, enhance bioenergetics, promote proliferation and invasion, induce drug resistance, and remodel TME by suppressing antitumor immunity. While previous reviews have predominantly focused on the role of mitochondrial transfer in individual cancers or specific systemic diseases, we made a comprehensive overview encompassing diverse cancer types. These findings suggest that EV-mediated mitochondrial cargo transfer represents a biological intercellular communication mechanism with implications for tumor progression and therapeutic resistance. It is worth noting that we also apply standardized evidence-grading frameworks (C1-C4) across cancer types to provide a critical assessment of the current evidence and identify key methodological gaps that must be addressed in future studies. Collectively, this review underscores the significance of EV-mediated mitochondrial transfer as an important biological process in cancer, presenting it as a promising frontier for novel diagnostic and therapeutic interventions.