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GLP1 alleviates oleic acid-propelled lipocalin-2 generation by tumor-infiltrating CD8+ T cells to reduce polymorphonuclear MDSC recruitment and enhances viral immunotherapy in pancreatic cancer

Cellular & Molecular Immunology volume 22, pages 282–299 (2025)Cite this article

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Abstract

Recruitment of polymorphonuclear MDSCs (PMN-MDSCs) in the TME suppresses the antitumor activity of tumor-infiltrating CD8+ T cells (CD8+ TILs). Little is known about the role of antitumoral CD8+ TILs in actively initiating an immune-tolerant microenvironment, particularly in the recruitment of PMN-MDSCs. In this study, we found that immunotherapy-activated CD8+ TILs significantly increased PNM-MDSC infiltration in the TME, resulting in antitumor resistance. When CD8+ T cells are activated, lipocalin-2 (LCN2) expression is strongly upregulated, which significantly enhances PMN-MDSC chemotaxis. Mechanistically, immune activation increased fatty acid synthesis in CD8+ T cells, particularly oleic acid (OA), which induced lysosomal membrane permeabilization, releasing cathepsin B and subsequently activating NF-κB to promote LCN2 expression. Moreover, we showed that glucagon-like peptide 1 (GLP1) effectively inhibited OA synthesis in activated CD8+ T cells, reducing LCN2 production. We then developed a recombinant adenovirus encoding GLP1 (AdV-GLP1), which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8+ TILs. In various pancreatic cancer models, including subcutaneous, orthotopic, and humanized CDX/PDX models, AdV-GLP1 displayed excellent antitumor efficacy. Our work advances the understanding of how immunotherapy-activated CD8+ TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improve cancer immunotherapy.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (82273261 to JW, 82073367 to MX), Nanjing University (0214/151130 to JW) and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (ZZYJ-202401 to JW). We are grateful to TissueGnostics Asia Pacific Ltd. for their technical support. We thank Dr. Hua Zhang (SPH Biotherapeutics (HK) Limited) for kindly providing the HPD-1NR cell line.

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  1. These authors contributed equally: Jingyi Wu, Peng Qian, Yifeng Han.

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China

    Jingyi Wu, Peng Qian, Yifeng Han, Chuning Xu, Jiwu Wei & Jie Dong

  2. Department of Clinical Laboratory Medicine, the Affiliated Hospital of Nantong University, Nantong, Jiangsu, China

    Mao Xia

  3. Department of Respiratory Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China

    Ping Zhan

  4. Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, Jiangsu, 226001, China

    Jie Dong

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  1. Jingyi Wu
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Contributions

JW and JD conceived the study, designed the experiments, and supervised the project. JW, PQ, YH, CX, and JD performed the experiments. JW, JD, PQ, MX, PZ, and JW analyzed the data. JW, JD, and JW wrote the original draft of the paper. All the authors critically reviewed and approved the manuscript.

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Correspondence to Jiwu Wei or Jie Dong.

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Wu, J., Qian, P., Han, Y. et al. GLP1 alleviates oleic acid-propelled lipocalin-2 generation by tumor-infiltrating CD8+ T cells to reduce polymorphonuclear MDSC recruitment and enhances viral immunotherapy in pancreatic cancer. Cell Mol Immunol 22, 282–299 (2025). https://doi.org/10.1038/s41423-025-01260-3

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