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

Han, Lijie, Gan, Lina, Schäfer, Balázs, Voss, Dillon M, Danielsen, Mathias, Kostov, Ondrej, Liu, Jia, Wang, Ting, Caruthers, Marvin H, Chen, Hao, Krainer, Adrian R (April 2026) ASO-based PKM splice-switching therapy increases anti-CTLA-4 antibody efficacy in pancreatic ductal adenocarcinoma. Cell Discovery, 12 (1). ISSN 2056-5968 (Public Dataset)

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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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > cancer > cancer types > pancreatic cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Inheritance Program
CSHL labs > Krainer lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 21 April 2026
Date Deposited: 22 Apr 2026 19:46
Last Modified: 22 Apr 2026 19:46
Related URLs:
Dataset ID:
URI: https://repository.cshl.edu/id/eprint/42174

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