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.

中文翻译：

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细胞自主的 IL6ST 激活通过 STAT3/ARF/p53 驱动的衰老抑制前列腺癌的发展，并赋予免疫活性肿瘤微环境


前列腺癌是全球男性中第二大最常见的癌症。最近的研究强调了 IL6ST 介导的信号通路在各种癌症的发生和发展中发挥的关键作用，特别是通过过度激活的 STAT3 信号传导。然而，人们对前列腺癌中 IL6ST/STAT3 介导的分子程序知之甚少。为了研究 IL6ST 信号传导的作用，我们在体内组成性激活了 Pten 缺陷型前列腺癌小鼠模型前列腺上皮中的 IL6ST 信号传导，并检测了 IL6ST 在大型前列腺癌患者队列中的表达。我们通过深入的转录组学和多重组织病理学分析补充了这些数据。前列腺上皮细胞中 IL6ST 受体的遗传细胞自主激活触发了活性 STAT3 信号传导，并显着减少了体内肿瘤生长。从机制上讲，IL6ST 信号转导的基因激活通过 STAT3/ARF/p53 轴介导衰老和细胞毒性 T 细胞的募集，最终阻碍肿瘤进展。在前列腺癌患者中，IL6ST mRNA 的高表达水平与更好的无复发生存期、衰老信号增加以及从免疫感冒到免疫热肿瘤的转变相关。我们的研究结果表明，IL6ST/STAT3 在癌变中具有上下文依赖性作用，并通过诱导衰老和免疫细胞吸引在前列腺癌发展中发挥肿瘤抑制功能。我们挑战了阻断 IL6ST/STAT3 信号传导作为功能性前列腺癌治疗的流行概念，而是提出细胞自主 IL6ST 激活作为一种新的治疗策略。