Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harbouring truncating mutations that prematurely terminate translation, including nonsense, frameshift and some splice-site mutations. Recent studies show that NMD shapes the mutational landscape of tumours by selecting for mutations that tend to downregulate the expression of tumour suppressor genes but not oncogenes. This suggests that NMD can benefit tumours, a notion further supported by the finding that mRNAs encoding immunogenic neoantigen peptides are typically targeted for decay by NMD. Together, this raises the possibility that NMD-inhibitory therapy could be of therapeutic benefit against many tumour types, including those with a high load of neoantigen-generating mutations. Complicating this scenario is the evidence that NMD can also be detrimental for many tumour types, and consequently tumours often have perturbed NMD. NMD may suppress tumour generation and progression by degrading subsets of specific normal mRNAs, including those encoding stress-response proteins, signalling factors and other proteins beneficial for tumours, as well as pro-tumour non-coding RNAs. Together, these findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types. However, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.

无义介导的 RNA 衰减 (NMD) 是一种高度保守的 RNA 周转途径，可选择性降解含有过早终止翻译的截短突变的 RNA，包括无义、移码和一些剪接位点突变。最近的研究表明，NMD 通过选择倾向于下调抑癌基因而非癌基因表达的突变来塑造肿瘤的突变格局。这表明 NMD 可以有益于肿瘤，编码免疫原性新抗原肽的 mRNA 通常是 NMD 降解的目标这一发现进一步支持了这一观点。总之，这提出了 NMD 抑制疗法可能对许多肿瘤类型具有治疗益处的可能性，包括那些具有大量新抗原生成突变的肿瘤。使这种情况变得复杂的是，有证据表明 NMD 对许多肿瘤类型也有害，因此肿瘤常常会扰乱 NMD。NMD 可能通过降解特定正常 mRNA 的子集来抑制肿瘤的生成和进展，这些 mRNA 包括编码应激反应蛋白、信号因子和其他对肿瘤有益的蛋白质，以及促肿瘤非编码 RNA。总之，这些发现表明 NMD 调节疗法有可能为多种肿瘤类型提供广泛的治疗益处。然而，是否应该刺激或抑制 NMD 需要对待治疗的肿瘤进行仔细分析。