Block, clear, and boost: a novel therapeutic framework for targeting intercellular mitochondrial transfer in Cancer immunotherapy.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Intercellular mitochondrial transfer (IMT) is emerging as a critical regulator of the tumor microenvironment, reshaping bioenergetics, signaling, and therapeutic responsiveness across the tumor-immune interface. Mitochondrial material can be exchanged within the tumor microenvironment (TME) through multiple routes, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction-associated exchange, and cell-cell fusion. The outcome of this exchange depends strongly on the quality of the transferred mitochondrial material: delivery of metabolically competent mitochondria may restore oxidative phosphorylation and effector function in T cells, whereas transfer of damaged mitochondrial cargo may amplify oxidative stress and promote terminal dysfunction. Mitochondrial quality-control mechanisms, including the PINK1-Parkin pathway and USP30-regulated deubiquitination, may critically influence how recipient cells process transferred mitochondrial material. Beyond adaptive immunity, IMT has also been implicated in innate immune compartments, including macrophages, natural killer cells, and dendritic cells. More broadly, cancer cells can acquire mitochondrial support from non-malignant partners, including neurons, adipose-derived stem cells, and endothelial cells, thereby enhancing metabolic flexibility, drug resistance, and metastatic potential in selected contexts. Ba

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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