Mitochondrial Transfer Between Cancer and T Cells: Implications for Immune Evasion

Abstract

Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer-T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response.

Keywords: MERCI methodology; T cell exhaustion; cancer metabolism; immune evasion; immunotherapy; mitochondrial transfer; oxidative stress; single-cell analysis; tumor microenvironment; tunneling nanotubes.

Figure 1

The dual role of intercellular mitochondrial transfer in the tumor microenvironment. This figure illustrates the opposing outcomes of mitochondrial transfer between cancer cells and T cells. (A) In a pathological context, cancer cells orchestrate immune evasion by hijacking functional mitochondria from T cells and, in turn, transferring dysfunctional mitochondria to induce T cell exhaustion. (B) In a therapeutic context, healthy donor cells, such as mesenchymal stromal cells (MSCs), can transfer functional mitochondria to exhausted T cells, leading to their metabolic revitalization and enhanced antitumor activity. Key mechanisms include tunneling nanotubes (TNTs) and extracellular vesicles (EVs). PD-1, Programmed cell death protein 1. Figure created in BioRender. mol, C. (2025). https://BioRender.com/z4rn9nb. The up and down arrows indicate increases and decreases, respectively.

Figure 2

Key mechanisms and molecular regulators of intercellular mitochondrial transfer. This figure illustrates the three primary pathways for mitochondrial transfer to a central recipient T cell: (1) tunneling nanotubes (TNTs), (2) extracellular vesicles (EVs), and (3) direct cell–cell contact via gap junctions. (1) TNTs are F-actin-based tubes that form direct cytoplasmic bridges. The transport of mitochondria along these actin tracks is an active process facilitated by motor proteins, with the adaptor protein Miro1 anchoring the mitochondria to the motor complex. The stability of the actin tracks requires the local inactivation of actin-depolymerizing factors like Cofilin. (2) EV-mediated transfer involves the packaging of mitochondria or their components into vesicles. The release of these EVs can be triggered by high concentrations of extracellular ATP, which activates the P2X7 receptor on the donor cell. (3) Direct transfer can occur through gap junction channels, composed of Connexin 43 (Cx43) proteins, which allow for the passage of organelles between adjacent cells, such as from a mesenchymal stromal cell (MSC) to a T cell. Each pathway contributes to the complex intercellular communication within the tumor microenvironment. Figure created in BioRender. mol, C. (2025). https://BioRender.com/go4stwh.