Targeting PKM2 Enhances the Anti-Tumor Function of CD8⁺ T Cells Through Metabolic Reprogramming.

Authors

Junxiu Zhang, Shuyi Wu, Qin Yin, Yanglin Liu, Shuguo Zheng, Peiwei Yang

Published in

International journal of molecular sciences. Volume 27. Issue 17. Aug 27, 2026. Epub Aug 27, 2026.

Abstract

The efficacy of adoptive cell transfer (ACT) therapy in solid tumors is often limited by the functional exhaustion and insufficient persistence of infused CD8⁺ T cells within the tumor microenvironment. Through the integrated analysis of single-cell transcriptomic data, this study identified enolase 1 (ENO1), a key rate-limiting enzyme in glycolysis, as a core gene highly correlated with the superior anti-tumor phenotype of tumor-infiltrating lymphocytes (TILs). However, in vitro functional validation demonstrated that the overexpression of Eno1 failed to substantially enhance the anti-tumor efficacy of mouse T cells, suggesting the presence of a downstream metabolic regulatory node within the glycolytic cascade that restricts the conversion of carbon flux. To overcome this limitation, we introduced the small molecule activator TEPP-46 to target a crucial downstream metabolic hub, pyruvate kinase M2 (PKM2). Transcriptome sequencing confirmed that PKM2 activation successfully induced systemic metabolic rewiring in CD8⁺ T cells and broadly upregulated the expression of cytotoxicity- and memory-related genes. In an in vivo B16-OVA melanoma model, OT-1 T cells subjected to In vitro TEPP-46 pretreatment exhibited significantly enhanced tumor-suppressive capabilities and effectively promoted the preferential differentiation of T cells into central memory T cells (Tcm). In summary, this study highlights the importance of targeting downstream metabolic nodes to bypass intrinsic metabolic restrictions in T cells. It demonstrates that in vitro metabolic pretreatment via PKM2 activation represents an effective translational strategy for optimizing the anti-tumor efficacy of ACT cell products.

PMID:
42737562
Bibliographic data and abstract were imported from PubMed on 11 Oct 2026.

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