April 29, 2025 | Austin, Minn. — Despite the massive successes of immunotherapy, which utilizes the body’s immune system as a tool to fight cancer, therapy resistance is still a common treatment obstacle for many patients with solid tumors. With a new paper in the leading scientific journal Cell Metabolism, the lab of Vivek Verma, PhD, assistant professor at The Hormel Institute, University of Minnesota, outlines a pharmacological method to boost mitochondrial function in cells that could be easily translated to clinics, enhancing immunotherapy treatments for better outcomes in patients.
“This study has huge implications in reversing the resistance of cancer patients to various immunotherapies,” Dr. Verma said. “Our study provides a direct link between cell metabolism and gene expression, especially in mitochondria.”
The cancerous tumor microenvironment is a hostile one, especially to an immune cell’s powerhouse: the mitochondria. Signals given off in this microenvironment can interfere with nutrition, inhibit mitochondrial function, and lead to immune cell exhaustion. With little to no energy, immune cells are unable to actively fight off pathogens, infections, and cancerous cells. Mitochondrial function is also essential for the process of T cells transitioning from their naive phase to the effector phase—when these immune cells begin actively fighting off pathogens or cancerous cells.
Currently, there are not yet any clinically viable strategies that can be used to target mitochondria to ensure it retains the power necessary to fight off disease, including cancer.
In the Cell Metabolism paper, Dr. Verma and the team found that activating the enzyme PKM2 helped boost mitochondrial metabolism in anti-tumor CD8 T cells. PKM2 plays a key role in the glycolytic pathway for ATP generation, which gives cells the energy they need to perform their necessary functions, and activating it means CD8 T Cells have the strength to battle cancer. Additionally, the team learned that CD8 T cells with activated PKM2 also displayed better efficacy in adoptive cell models and in combination with immune checkpoint-based immunotherapy.
“Surprisingly, the roles of PKM2 in CD8 T cells had not yet been established. In this study, we show for the first time that pharmacological activation of PKM2 leads to mitochondria-mediated enhancement of effector functions in CD8 T cells,” Dr. Verma said. “Also surprisingly, we found that PKM2 modifies cell metabolism that regulates the expression of genes located on mitochondrial DNA. Our study provides a direct link between cell metabolism and gene expression, especially in mitochondria.”
Other findings from the study include:
- Activated PKM2 supports CD8 T cell activation and effector functions.
- PKM2 reprograms cell metabolome (small-molecule chemicals within a cell) and epigenome (chemical compounds that can attach to DNA and direct certain functions), enhancing mitochondrial translation.
- PKM2 activation in CD8 and CAR-T cells increases the cells’ anti-tumor activity.
- Pharmacological agonism of PKM2 enhances efficacy of anti-PD1, a form of immunotherapy.
The Hormel Institute’s scientists Post-Doctoral Associate Seyedeh Sahar Mortazavi Farsani, PhD; Post-Doctoral Associate Jignesh Soni, PhD; Researcher 5 Lu Jin; Post-Doctoral Associate Anil Kumar Yadav, PhD; Professor Leena Hilakivi-Clarke, PhD; and Executive Director Robert Clarke, PhD, are also listed as authors of the paper.
You can read the paper here: https://doi.org/10.1016/j.cmet.2025.03.003
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The Hormel Institute is an independent biomedical research department within the University of Minnesota’s Office of the Vice President for Research. Collaborative research partners include Masonic Cancer Center UMN (a Comprehensive Cancer Center as designated by the National Cancer Institute, NIH), Mayo Clinic, and many other leading research centers worldwide. The Hormel Institute, which tripled in size in 2008 and doubled again in size in 2016, is home to some of the world’s most cutting-edge research technologies and expert scientists. Over the next few years, The Hormel Institute will broaden its impact through innovative, world-class research in its quest to improve human health.