通过内在核糖体移码实现癌症选择性基因回路
通过内在核糖体移码实现癌症选择性基因回路
作者： 小柯机器人 发布时间：2026/11/15 19:58:37
本期文章：《自然》：Online/在线发表
2026年11月4日，浙江大学附属第二医院Mao Yuanhui等科学家在《自然》发表研究，利用癌细胞中内在的核糖体移码特性构建了癌症选择性基因回路。
核糖体移码是一种不常见的翻译重编码事件，最著名的是其在病毒基因表达中的调控作用，而其在哺乳动物中的生理相关性仍知之甚少。在此，研究人员表明，特定密码子对优先在癌细胞中触发有效的1位移码。机制上，这种重编码源于与tRNA和氨基酸可用性相关的核糖体暂停，并被受损的核糖体质量控制和核糖体蛋白S6的持续磷酸化所放大。研究人员发现，这种密码子对特异性移码代表了一种翻译失调的内在状态，该状态在癌细胞中普遍存在并重塑蛋白质合成。利用癌细胞中这种允许移码的状态，研究人员工程化了一种移码激活的合成治疗回路（FAST），该回路条件性表达焦亡效应因子gasdermin D。FAST在多种癌细胞类型中被激活，诱导强效且选择性的细胞焦亡，同时使正常组织免于可检测的毒性。作为概念验证，在结直肠癌和胰腺癌小鼠模型中全身性AAV9介导的FAST递送引发了显著的肿瘤消退、强烈的免疫激活以及与免疫检查点阻断的协同效应。总之，这些发现揭示了密码子对依赖性核糖体移码是癌细胞翻译失调的一个特征，并确立了翻译偶联基因回路作为癌症选择性治疗的一种策略。
附：英文原文
Title: Cancer-selective gene circuits via intrinsic ribosomal frameshifting
Author: Wang, Qiuyi, Chen, Ao, Liu, Yaoqi, Yu, Xiaoxiao, Zhang, Hao, Yu, Yuqiang, Chen, Pengyu, Zhang, Yue, Chan, Francis Ka-Ming, Gao, Xiangwei, Mao, Yuanhui
Issue&Volume: 2026-11-04
Abstract: Ribosomal frameshifting, an uncommon translational recoding event, is best known for its regulatory roles in viral gene expression1,2, whereas its physiological relevance in mammals remains poorly understood. Here we show that specific codon pairs trigger efficient 1 frameshifting preferentially in cancer cells. Mechanistically, this recoding arises from ribosomal pausing associated with tRNA and amino acid availability, and is amplified by impaired ribosome quality control and sustained phosphorylation of ribosomal protein S6. We found that this codon-pair-specific frameshifting represents an intrinsic state of translational dysregulation, which is prevalent across cancer cells and reshapes protein synthesis. Taking advantage of this frameshifting-permissive state in cancer cells, we engineered a frameshifting-activated synthetic therapeutic circuit (FAST) that conditionally expresses the pyroptotic effector gasdermin D. FAST is activated across diverse cancer cell types, inducing potent and selective pyroptosis, while sparing normal tissues from detectable toxicity. As a proof of concept, systemic AAV9-mediated delivery of FAST in mouse models of colorectal and pancreatic cancer elicited pronounced tumour regression, robust immune activation and synergistic effects with immune checkpoint blockade. Collectively, these findings reveal codon-pair-dependent ribosomal frameshifting as a feature of translational dysregulation in cancer cells and establish translation-coupled gene circuits as a strategy for cancer-selective therapy.
DOI: 10.1038/s41586-026-11200-4
Source: https://www.nature.com/articles/s41586-026-11200-4
主题：一种