Activated CD8+ T cells increase mitochondrial mass and membrane potential to generate the energy needed for their work. As might be expected, dysfunctional and depolarized mitochondria are associated with T cell exhaustion and have been the focus of many tumor immunology studies. But poor mitochondrial quality and efficiency in T cells can also cause abnormally elevated membrane potential, or hyperpolarization, of mitochondria. In fact, studies of adoptive cell therapy in preclinical models have shown T cells with low mitochondrial potential to be associated with memory phenotype and improved effector function and those with high potential to have better initial effector function but a propensity for exhaustion and shorter survival. Researchers led by Ludwig Chicago Co-director Jeffrey Rathmell and his Vanderbilt University colleague Kathryn Beckermann assessed the mitochondrial membrane potential (MMP) of tumor-associated T cells in the peripheral circulation as an indicator of T cell phenotypes and a marker of responses to immune checkpoint inhibitors (ICIs) in non-small cell lung carcinoma and clear cell renal cell carcinoma patients. They reported in a June issue of The Journal of Immunology that MMPhigh CD8+ T cells tended to be exhausted, while those in an MMPlow state were more often memory cells. They also identified gene signatures associated with anti-tumor MMPhigh T cells that are negatively correlated with patient response to ICIs and could be biomarkers of T cell exhaustion.
Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy
The Journal of Immunology, 2026 June 17