Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment

Sep 21, 2026

Uploaded by Skyler

Prostate cancer remains the second most frequently diagnosed cancer in men worldwide, and IL6ST-mediated signaling—especially hyperactivated STAT3—has been implicated in cancer progression. However, the molecular programs driven by IL6ST/STAT3 in prostate cancer are insufficiently defined. Constitutive IL6ST activation in prostate epithelium of a Pten-deficient mouse model, combined with cohort patient profiling, transcriptomics, and multiplex histopathology, links IL6ST/STAT3 activity to senescence through STAT3/ARF/p53 and cytotoxic T-cell recruitment, leading to reduced tumor growth and improved recurrence-free survival.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Keywords

Background

Rationale and disease context

IL6ST/STAT3 axis in prostate cancer

Sternberg et al. Molecular Cancer (2024) 23:245 [https://doi.org/10.1186/s12943-024-02114-8](https://doi.org/10.1186/s12943-024-02114-8) Molecular Cancer RESEARCH Open Access Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment Christina Sternberg1,2,3*, Martin Raigel 1,3,4, Tanja Limberger 1,4,5, Karolína Trachtová4,6, Michaela Schlederer1, Desiree Lindner3, Petra Kodajova3, Jiaye Yang1, Roman Ziegler3,17, Jessica Kalla 1, Stefan Stoiber 1,4,7, Saptaswa Dey8, Daniela Zwolanek9, Heidi A. Neubauer 10,18, Monika Oberhuber5, Torben Redmer3, Václav Hejret6, Boris Tichy6, MartinaTomberger5, Nora S. Harbusch5, Jan Pencik 1, Simone Tangermann3, Vojtech Bystry6, Jenny L. Persson 11,12, Gerda Egger 1,13, Sarka Pospisilova6, Robert Eferl9, Peter Wolf8,14, Felix Sternberg15,16, Sandra Högler3, Sabine Lagger3, Stefan Rose-John2*† and Lukas Kenner 1,3,5,7,13*† Abstract Background 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. Methods 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. Results 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. †Stefan Rose-John and Lukas Kenner co-last authors. *Correspondence: Christina Sternberg [christina.sternberg@meduniwien.ac.at](christina.sternberg@meduniwien.ac.at)[ ](christina.sternberg@meduniwien.ac.at)Stefan Rose-John [rosejohn@biochem.uni-kiel.de](rosejohn@biochem.uni-kiel.de)[ ](rosejohn@biochem.uni-kiel.de)Lukas Kenner [lukas.kenner@meduniwien.ac.at](lukas.kenner@meduniwien.ac.at) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/.)[.](http://creativecommons.org/licenses/by-nc-nd/4.0/.) Sternberg et al. Molecular Cancer (2024) 23:245 Page 2 of 22 Conclusions Our fin

FAQs

What was the main goal of the study on IL6ST in prostate cancer?

The study aimed to determine how IL6ST signaling contributes to prostate cancer development and progression, focusing on molecular programs mediated by IL6ST/STAT3 and related pathways.

How did the researchers test the role of IL6ST signaling?

They constitutively activated IL6ST signaling in prostate epithelium in vivo using a Pten-deficient mouse model, assessed IL6ST expression in large patient cohorts, and combined these data with transcriptomic and multiplex histopathological analyses.

What mechanisms did the study identify linking IL6ST activation to tumor suppression?

Genetic, cell-autonomous IL6ST receptor activation triggered active STAT3 signaling, promoted senescence via the STAT3/ARF/p53 axis, and increased recruitment of cytotoxic T-cells, collectively impeding tumor progression.

Sep 21, 2026

Uploaded by Skyler