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. 2025 Jun 3;37(6):1294-1310.e7.
doi: 10.1016/j.cmet.2025.03.003. Epub 2025 Apr 7.

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Seyedeh Sahar Mortazavi Farsani  1 , Jignesh Soni  1 , Lu Jin  1 , Anil Kumar Yadav  1 , Shivani Bansal  2 , Tian Mi  3 , Leena Hilakivi-Clarke  1 , Robert Clarke  1 , Benjamin Youngblood  3 , Amrita Cheema  2 , Vivek Verma  4
Affiliations

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Seyedeh Sahar Mortazavi Farsani et al. Cell Metab. .

Abstract

Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy. VIDEO ABSTRACT.

Keywords: CD8 T cells; PD1 blockade; PKM2; adoptive cell therapy; immunotherapy; melanoma; metabolism; mitochondria.

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Conflict of interest statement

Declaration of interests We declare that a patent entitled “Pharmacological enhancement of CD8 T cell effector function using TEPP46” has been filed by the University of Minnesota based on the work performed in the current manuscript. Technology no. 2022-294. IP status: provisional patent application filed.

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