Mitochondrial transfer: a microenvironmental determinant of tumor evolution and therapeutic vulnerability

The tumor microenvironment (TME) comprises tumor cells, immune cells, fibroblasts, endothelial cells, mesenchymal stem cells, and non-cellular components such as the extracellular matrix and soluble factors. Through intercellular material exchange and signaling, the TME profoundly influences tumor growth, invasion, metastasis, immune evasion, and therapeutic resistance. Among the diverse forms of intercellular communication within the TME, mitochondrial transfer has garnered increasing attention. Here, we synthesize recent advances in mitochondrial transfer within the TME across three levels: transfer mechanisms, biological consequences, and therapeutic implications. We first outline the principal routes of mitochondrial transfer, including tunneling nanotubes, gap junctions, cell fusion, extracellular vesicles, and free mitochondria. We then examine how mitochondrial transfer contributes to tumor progression, therapeutic resistance, and immune regulation. Finally, we discuss the emerging therapeutic opportunities and potential challenges for clinical translation. Deeper insight into mitochondrial transfer within the TME may provide new opportunities for constraining tumor evolution, overcoming treatment resistance, and developing innovative therapies.