Yabo Zhou # 1, Dianheng Wang # 1, Shujing Wang # 1, Chaoying Zhang 1, Lina He 1, Youli Kang 1, Wu Yuan 1, Andrew Nguyen 1, Jie Chen 1, Nannan Zhou 1, Li Zhou 1, Zhenfeng Wang 1, Chaoqi Zhang 1 2, Tuying Yong 3, Ke Tang 4, Huafeng Zhang 5, Jingwei Ma 6, Jiadi Lv 7, Bo Huang 8 9

Cell Mol Immunol. 2026 Mar;23(3):329-343.

PMID: 41617981 PMCID: PMC12949050 (available on 2027-03-01) DOI: 10.1038/s41423-026-01390-2

Abstract

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.

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