Christina Sternberg Christina Sternberg Martin Raigel Martin Raigel Tanja Limberger Tanja Limberger Karolína Trachtová Karolína Trachtová Michaela Schlederer Michaela Schlederer Desiree Lindner Desiree Lindner Petra Kodajova Petra Kodajova Jiaye Yang Jiaye Yang Roman Ziegler Roman Ziegler Jessica Kalla Jessica Kalla Stefan Stoiber Stefan Stoiber Saptaswa Dey Saptaswa Dey Daniela Zwolanek Daniela Zwolanek Heidi A Neubauer Heidi A Neubauer Monika Oberhuber Monika Oberhuber Torben Redmer Torben Redmer Václav Hejret Václav Hejret Boris Tichy Boris Tichy Martina Tomberger Martina Tomberger Nora S. Harbusch Nora S. Harbusch Jan Pencik Jan Pencik Simone Tangermann Simone Tangermann Vojtech Bystry Vojtech Bystry Jenny L Persson Jenny L Persson Gerda Egger Gerda Egger Sarka Pospisilova Sarka Pospisilova Robert Eferl Robert Eferl Peter Wolf Peter Wolf Felix Sternberg Felix Sternberg Sandra Högler Sandra Högler Sabine Lagger Sabine Lagger Stefan Rose-John Stefan Rose-John Lukas Kenner Lukas Kenner BMC 2024 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. PDFDocument eng 2024-12-10T15:42:26.736559Z 2024 Prostate Cancer IL6ST/STAT3 Signaling L-gp130 Senescence Senescence-associated Secretory Phenotype Tumor Microenvironment Immune Cell Infiltration Cytotoxic T-Cells 11214276 b application/pdf application/pdf http://creativecommons.org/licenses/by-nc-nd/4.0/