Core Viewpoint - Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and resistant to conventional therapies, with tumor-repopulating cells (TRC) identified as key factors in treatment failure and recurrence [2][3] Group 1: Research Findings - TRC possess stem cell-like properties, enabling them to initiate tumor formation and evade T cell attacks, contributing to PDAC's aggressive nature [2] - The research team led by Huang Bo discovered that PDAC cells express high levels of gasdermin E (GSDME), which promotes mucin expression through the GSDME-YBX1-mucin pathway, allowing tumor cells to survive in the pancreatic microenvironment [2][3] - A combination therapy using interferon-gamma (IFN-γ), interferon-beta (IFN-β), and transforming growth factor-beta (TGF-β) can restore GSDME's classical function, inducing a novel lysosome-dependent killing mechanism [3][5] Group 2: Mechanism of Action - The therapy utilizes an mRNA-LNP delivery system to express the three cytokines, leading to GSDME's phosphorylation and translocation to lysosomes, where it is activated by cathepsin D [3][5] - Phosphorylated GSDME forms pores in the lysosomal membrane, causing lysosomal rupture and specifically eliminating TRC in PDAC [5][6] Group 3: Therapeutic Potential - The mRNA-LNP therapy demonstrated efficacy in mouse models of PDAC, highlighting its translational application potential for patients [4][6] - TRC exhibit higher expression levels of GSDME and receptors for the three cytokines, making them more sensitive to the combined intervention therapy [6] - The IIT-LNP system not only targets TRC to halt tumor progression but also converts "cold tumors" into "hot tumors," enhancing the overall anti-cancer effect [6]