ASO-based PKM splice-switching therapy increases anti-CTLA-4 antibody efficacy in pancreatic ductal adenocarcinoma

  • Cell Discov. 2026 Apr 21;12(1):28. doi: 10.1038/s41421-026-00882-9.
Lijie Han  #  1  2 ,  Lina Gan  #  2 ,  Balázs Schäfer  3 ,  Dillon M Voss  1  4 ,  Mathias Danielsen  3 ,  Ondrej Kostov  3 ,  Jia Liu  2 ,  Ting Wang  5 ,  Marvin H Caruthers  3 ,  Hao Chen  6 ,  Adrian R Krainer  7
Affiliations
  • 1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • 2. Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 3. Department of Biochemistry, University of Colorado, Boulder, CO, USA.
  • 4. Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • 5. Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
  • 7. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. [email protected].
  • # Contributed equally.
PMID: 42009652 DOI: 10.1038/s41421-026-00882-9
Abstract

The alternative splice isoform of Pyruvate Kinase M (PKM), PKM2, plays a pivotal role in regulating aerobic glycolysis in tumor cells. Systemic delivery of Antisense Oligonucleotides (ASOs) that shift PKM splicing from the PKM2 isoform to the PKM1 isoform inhibits tumor progression and reprograms intratumoral metabolism. However, the cellular populations within the tumor microenvironment (TME) are also highly dependent on PKM2 and might likewise be affected by ASO treatment. In this study, we demonstrate that PKM2 is upregulated and PKM1 is downregulated in both human and murine pancreatic ductal adenocarcinoma (PDAC) cells. PKM1 and PKM2 are mutually exclusive and expressed in a cell type-specific manner in various cell types and stages of PDAC tumors. We report that basal-like PDAC cells and their surrounding activated regulatory T cells (Tregs) rely on PKM2 to sustain glycolysis. Although PKM-ASO monotherapy had a limited effect in an immunodeficient mouse model of PDAC, synergy between PKM-ASO and anti-CTLA-4 immune checkpoint blockade (ICB), which targets Tregs, restricted tumor growth in an immunocompetent mouse model. Our findings provide preclinical support for combined antisense therapy and ICB for PDAC patients, highlighting the critical role of PKM2 in the TME and its potential as a therapeutic target.

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