Systematic Review: Intercellular Mitochondrial Transfer in Melanoma Progression and ResistanceMitochondrial Transfer Fuels Melanoma Resistance and Spread

Intercellular mitochondrial transfer has emerged as a novel mode of metabolic communication, enabling the exchange of functional mitochondria and their associated components between cells via tunneling nanotubes, extracellular vesicles, and direct cell–cell contact. Melanoma is a highly aggressive malignancy characterized by remarkable metabolic plasticity, in which disease progression and therapeutic resistance are closely linked to mitochondrial reprogramming. Accumulating evidence indicates that, under conditions of therapeutic pressure or metabolic impairment, melanoma cells can acquire exogenous mitochondria to restore oxidative phosphorylation (OXPHOS), maintain redox homeostasis, and enhance survival. This process contributes to resistance to targeted therapies, immune evasion, and increased invasive and metastatic potential. Conversely, in specific contexts, intercellular mitochondrial transfer may exert tumor-suppressive effects by enhancing the metabolic fitness of immune cells, activating innate immune signaling pathways, or inducing oxidative stress–mediated apoptosis. These findings underscore the context-dependent nature of its biological effects, which are governed by factors such as donor and recipient cell identity, mitochondrial integration status, and microenvironmental stress conditions. In this review, we systematically summarize the principal mechanisms of intercellular mitochondrial transfer and highlight its bidirectional roles in melanoma progression and therapeutic resistance. Furthermore, we propose a context-dependent regulatory framework and discuss potential intervention strategies. A deeper understanding of this process may provide new theoretical insights for integrating metabolic modulation with targeted and immunotherapeutic approaches in precision melanoma treatment.