https://phaidra.vetmeduni.ac.at/o:3743 Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment Sternberg, Christina Christina Sternberg Raigel, Martin Martin Raigel Limberger, Tanja Tanja Limberger Trachtová, Karolína Karolína Trachtová Schlederer, Michaela Michaela Schlederer Lindner, Desiree Desiree Lindner Kodajova, Petra Petra Kodajova Yang, Jiaye Jiaye Yang Ziegler, Roman Roman Ziegler Kalla, Jessica Jessica Kalla Stoiber, Stefan Stefan Stoiber Dey, Saptaswa Saptaswa Dey Zwolanek, Daniela Daniela Zwolanek Neubauer, Heidi A Heidi A Neubauer 0000-0001-7372-7786 Oberhuber, Monika Monika Oberhuber Redmer, Torben Torben Redmer 0000-0002-0050-9478 Hejret, Václav Václav Hejret Tichy, Boris Boris Tichy Tomberger, Martina Martina Tomberger Harbusch, Nora S. Nora S. Harbusch Pencik, Jan Jan Pencik Tangermann, Simone Simone Tangermann Bystry, Vojtech Vojtech Bystry Persson, Jenny L Jenny L Persson Egger, Gerda Gerda Egger Pospisilova, Sarka Sarka Pospisilova Eferl, Robert Robert Eferl Wolf, Peter Peter Wolf Sternberg, Felix Felix Sternberg Högler, Sandra Sandra Högler 0000-0002-6899-5273 Lagger, Sabine Sabine Lagger 0000-0002-3032-9910 Rose-John, Stefan Stefan Rose-John Kenner, Lukas Lukas Kenner 0000-0003-2184-1338 BMC journal article open access eng Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood.To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses.Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor.Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy. Prostate Cancer IL6ST/STAT3 Signaling L-gp130 Senescence Senescence-associated Secretory Phenotype Tumor Microenvironment Immune Cell Infiltration Cytotoxic T-Cells http://creativecommons.org/licenses/by-nc-nd/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3743/download 10.1186/s12943-024-02114-8 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Molecular Cancer issn:1476-4598 VoR Molecular Cancer 23 1 10.69 MB 2024