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<p>Despite the pleiotropic capacities of cytokines in modulating cell behaviors, their therapeutic application in cancer remains challenging. Here, we show that the IFN-γ/IFN-β/TGF-β cocktail integrates these three signals with a cytosolic pore-forming protein, gasdermin E (GSDME), and synergistically drives its delivery into the lysosomes of pancreatic adenocarcinoma (PDAC) tumor-repopulating cells (TRCs), where GSDME is cleaved to mediate lysosomal pore formation. Mechanistically, IFN-γ signaling phosphorylates GSDME, enabling phosphorylated GSDME (p-GSDME) to bind the Golgi transmembrane protein TMED10 and subsequently traffic to lysosomes, where cathepsin D cleaves it into active N-GSDME, which induces lysosomal decomposition in TRCs. In parallel, IFN-β activates STAT1/STAT3 to upregulate cathepsin D expression, whereas TGF-β enhances GSDME phosphorylation by downregulating PPP1R3G, a regulatory subunit of protein phosphatase 1. Using lipid-hybrid nanoparticle–delivered mRNA technology, the tri-cytokine cocktail demonstrated therapeutic efficacy against orthotopic PDAC in mice and PDX models, highlighting its translational potential for PDAC patients.</p>

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Gasdermin E-mediated lysosome-pore formation curbs pancreatic ductal adenocarcinoma via IFN-γ/IFN-β/TGF-β cocktail mRNA-LNP

  • 期刊论文

  • 发表日期：

    2026年1月30日

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  • Yabo Zhou,
  • Dianheng Wang,
  • Shujing Wang,
  • Chaoying Zhang,
  • Lina He,
  • Youli Kang,
  • Wu Yuan,
  • Andrew Nguyen,
  • Jie Chen,
  • Nannan Zhou,
  • Li Zhou,
  • Zhenfeng Wang,
  • Chaoqi Zhang,
  • Tuying Yong,
  • Ke Tang,
  • Huafeng Zhang,
  • Jingwei Ma,
  • Jiadi Lv,
  • Bo Huang

摘要

Despite the pleiotropic capacities of cytokines in modulating cell behaviors, their therapeutic application in cancer remains challenging. Here, we show that the IFN-γ/IFN-β/TGF-β cocktail integrates these three signals with a cytosolic pore-forming protein, gasdermin E (GSDME), and synergistically drives its delivery into the lysosomes of pancreatic adenocarcinoma (PDAC) tumor-repopulating cells (TRCs), where GSDME is cleaved to mediate lysosomal pore formation. Mechanistically, IFN-γ signaling phosphorylates GSDME, enabling phosphorylated GSDME (p-GSDME) to bind the Golgi transmembrane protein TMED10 and subsequently traffic to lysosomes, where cathepsin D cleaves it into active N-GSDME, which induces lysosomal decomposition in TRCs. In parallel, IFN-β activates STAT1/STAT3 to upregulate cathepsin D expression, whereas TGF-β enhances GSDME phosphorylation by downregulating PPP1R3G, a regulatory subunit of protein phosphatase 1. Using lipid-hybrid nanoparticle–delivered mRNA technology, the tri-cytokine cocktail demonstrated therapeutic efficacy against orthotopic PDAC in mice and PDX models, highlighting its translational potential for PDAC patients.