Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell–intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27–dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.

中文翻译：

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STAT3/p53 通路激活破坏 IFN-β 诱导的肿瘤再生细胞休眠

与免疫系统的动态相互作用深刻调节肿瘤细胞休眠。然而，目前尚不清楚免疫信号如何触发癌细胞进入休眠的内在信号通路。在这里，我们发现 IFN-β 治疗通过吲哚胺 2,3-双加氧酶/犬尿氨酸/芳烃受体/p27 依赖性（IDO/Kyn/AhR/p27 依赖性）途径诱导肿瘤再生细胞 (TRC) 进入休眠状态。阻断这种代谢回路的策略并没有解除休眠，而是导致小鼠和人类黑色素瘤模型中休眠的 TRC 凋亡。具体来说，阻断 AhR 将 IFN-β 信号传导通过酪氨酸和丝氨酸位点重定向至 STAT3 磷酸化，随后促进 STAT3 核转位并随后与细胞核中的 p53 启动子结合。p53 的上调反过来又破坏了磷酸戊糖途径，导致 ROS 产生过多和休眠 TRC 死亡。此外，在黑色素瘤患者中，IFN-β的高表达与肿瘤细胞休眠相关。识别 IFN-β 控制 TRC 休眠的机制可以更深入地了解癌症-免疫相互作用和潜在的新癌症免疫治疗方式。