Targeting the mitochondrial transfer axis in cancer: From mechanistic insights to therapeutic rewiring

Intercellular mitochondrial transfer is emerging as a therapeutic target in cancer. It drives a bidirectional metabolic-immune axis that fuels tumor progression and immune evasion. This review frames cancer as a rewired mitochondrial ecosystem. In this ecosystem, forward transfer (stroma→cancer) fuels proliferation and therapy resistance, while reverse transfer (cancer→immune) induces T-cell exhaustion. We highlight host metabolism (e.g., obesity) as a key modulator. Therapeutically, we chart a shift from inhibiting detrimental transfer (e.g., targeting Miro1/USP30) toward actively delivering functional mitochondria to immune cells. Integrating spatial multi-omics, AI, and advanced imaging will enable mitochondria-centric precision oncology. This approach moves beyond inhibition to active remodeling of the tumor microenvironment. This synthesis provides a pharmacological roadmap for targeting mitochondrial transfer to disrupt tumor-stroma-immune crosstalk and enhance therapeutic efficacy.