Mitochondrial transfer in cancer: mechanisms, immune evasion, and therapeutic opportunities

Intercellular mitochondrial transfer (MT) is emerging as a transformative communication axis in cancer biology. Intact mitochondria or mitochondrial components can be exchanged between tumor cells, stromal elements, and immune cells via tunneling nanotubes, extracellular vesicles, cell fusion, or phagocytic uptake. This organelle exchange enables metabolic adaptation by restoring OXPHOS (oxidative phosphorylation), increasing ATP production, and enhancing survival in hostile environments. Conversely, tumor cells also hijack mitochondria from cytotoxic lymphocytes thereby undermining immune function and contributing to immune escape and tumor progression. These converging metabolic exchanges fuel immune evasion, metastatic potential, and resistance to chemotherapy, radiation, and immunotherapy. Cutting-edge tracing tools, including mitochondrial reporter proteins and single-cell mitochondrial genome lineage mapping, have uncovered MT events both in vitro and in vivo. Therapeutic strategies designed to block mitochondrial trafficking, inhibit nanotube formation or vesicle uptake, or enhance immune cell mitochondrial resilience hold promise for tumor sensitization and restoration of antitumor immunity. A deeper understanding of MT provides novel insight into cancer metabolism and intercellular communication, offering a foundation for future therapeutic innovation and potential clinical application as both a biomarker and a therapeutic target.