Department of Biochemistry, Purdue University, West Lafayette, IN, U.S.A.
Biochem Soc Trans. 2024 Oct 30;52(5):2035-2045. doi: 10.1042/BST20230727.
Immunotherapy has emerged as a therapeutic option for many cancers. For some tumors, immune checkpoint inhibitors show great efficacy in promoting anti-tumor immunity. However, not all tumors respond to immunotherapies. These tumors often exhibit reduced inflammation and are resistant to checkpoint inhibitors. Therapies that turn these 'cold' tumors 'hot' could improve the efficacy and applicability of checkpoint inhibitors, and in some cases may be sufficient on their own to promote anti-tumor immunity. One strategy to accomplish this goal is to activate innate immunity pathways within the tumor. Here we describe how this can be accomplished by activating double-stranded RNA (dsRNA) sensors. These sensors evolved to detect and respond to dsRNAs arising from viral infection but can also be activated by endogenous dsRNAs. A set of proteins, referred to as suppressors of dsRNA sensing, are responsible for preventing sensing 'self' dsRNA and activating innate immunity pathways. The mechanism of action of these suppressors falls into three categories: (1) Suppressors that affect mature RNAs through editing, degradation, restructuring, or binding. (2) Suppressors that affect RNA processing. (3) Suppressors that affect RNA expression. In this review we highlight suppressors that function through each mechanism, provide examples of the effects of disrupting those suppressors in cancer cell lines and tumors, and discuss the therapeutic potential of targeting these proteins and pathways.
免疫疗法已成为许多癌症的治疗选择。对于一些肿瘤，免疫检查点抑制剂在促进抗肿瘤免疫方面显示出很大的疗效。然而，并非所有的肿瘤都对免疫疗法有反应。这些肿瘤通常表现出炎症减少，并且对检查点抑制剂有抗性。使这些“冷”肿瘤“热”起来的疗法可以提高检查点抑制剂的疗效和适用性，在某些情况下，单独使用这些疗法就足以促进抗肿瘤免疫。实现这一目标的一种策略是激活肿瘤内的先天免疫途径。在这里，我们描述了如何通过激活双链 RNA (dsRNA) 传感器来实现这一目标。这些传感器的进化是为了检测和响应来自病毒感染的 dsRNA，但也可以被内源性 dsRNA 激活。一组被称为 dsRNA 感应抑制物的蛋白质负责防止感应“自身”dsRNA 并激活先天免疫途径。这些抑制剂的作用机制分为三类：(1) 通过编辑、降解、重构或结合来影响成熟 RNA 的抑制剂。(2) 影响 RNA 加工的抑制剂。(3) 影响 RNA 表达的抑制剂。在这篇综述中，我们重点介绍了通过每种机制发挥作用的抑制剂，提供了在癌细胞系和肿瘤中破坏这些抑制剂的影响的例子，并讨论了靶向这些蛋白质和途径的治疗潜力。
