Therapy-induced senescent tumor cells have emerged as significant drivers of tumor recurrence and disease relapse. Interestingly, reactive oxygen species (ROS) production and its associated redox signaling networks are intertwined with initiation and establishment of therapy-induced senescence. Therapy-induced senescent cells influence neighboring cells and the tumor microenvironment via their bioactive secretome known as the senescence-associated secretory phenotype (SASP). The intracellular effects of ROS are dose and context-dependent. Under normal physiological conditions, ROS is involved in various signalling pathways and cellular processes important for maintenance of cellular homeostasis, such as redox balance, stress response, inflammatory signalling, cell proliferation and cell death among others. However excess ROS accompanied by a pro-oxidant microenvironment can engender oxidative DNA damage, triggering cellular senescence. In this review, we discuss the role of ROS and the redox state dynamics in fine-tuning homeostatic processes that drive therapy-induced cell fate towards senescence establishment, as well as their influence in stimulating inflammatory signalling and SASP production. We also offer insights into interventional strategies, specifically senotherapeutics, that could potentially leverage on modulation of redox and antioxidant pathways. Lastly, we evaluate possible implications of redox rewiring during escape from therapy-induced senescence, an emerging area of research. We envision that examining therapy-induced senescence through the redox lens, integrated with time-resolved single-cell RNA sequencing combined with spatiotemporal multi-omics, could further enhance our understanding of its functional heterogeneity. This could aid identification of targetable signalling nodes to reduce disease relapse, as well as inform strategies for development of broad-spectrum senotherapeutics. Overall, our review aims to delineate redox-driven mechanisms which contribute to the biology of therapy-induced senescence and beyond, while highlighting implications for tumor initiation and recurrence.

中文翻译：

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通过氧化还原晶状体治疗诱导的衰老


治疗诱导的衰老肿瘤细胞已成为肿瘤复发和疾病复发的重要驱动因素。有趣的是，活性氧（ROS）的产生及其相关的氧化还原信号网络与治疗诱导的衰老的启动和建立交织在一起。治疗诱导的衰老细胞通过其生物活性分泌组（称为衰老相关分泌表型（SASP））影响邻近细胞和肿瘤微环境。 ROS 的细胞内作用具有剂量和环境依赖性。在正常生理条件下，ROS参与对维持细胞稳态很重要的各种信号传导途径和细胞过程，例如氧化还原平衡、应激反应、炎症信号传导、细胞增殖和细胞死亡等。然而，过量的 ROS 和促氧化微环境会导致 DNA 氧化损伤，引发细胞衰老。在这篇综述中，我们讨论了 ROS 和氧化还原态动力学在微调稳态过程中的作用，这些稳态过程驱动治疗诱导的细胞命运走向衰老建立，以及它们在刺激炎症信号传导和 SASP 产生中的影响。我们还提供了对干预策略的见解，特别是治疗方法，可能会利用氧化还原和抗氧化途径的调节。最后，我们评估了氧化还原重新布线在逃避治疗引起的衰老过程中可能产生的影响，这是一个新兴的研究领域。我们设想，通过氧化还原透镜检查治疗引起的衰老，结合时间分辨单细胞 RNA 测序和时空多组学，可以进一步增强我们对其功能异质性的理解。 这可以帮助识别可靶向的信号节点以减少疾病复发，并为广谱治疗药物的开发策略提供信息。总体而言，我们的综述旨在描绘氧化还原驱动的机制，这些机制有助于治疗引起的衰老及其他生物学作用，同时强调对肿瘤发生和复发的影响。