FAST circuit exploits ribosomal frameshifting in cancer cells; tumours regress in mice
Authors found that specific codon pairs cause −1 ribosomal frameshifting mainly in cancer cells and used it to switch on a pyroptosis gene in mouse tumour models.
A team led by Q. Wang reports in Nature (2026, doi.org/10.1038/s41586-026-11200-4) that specific codon pairs trigger efficient −1 ribosomal frameshifting preferentially in cancer cells doi.org
doi.orgdoi.orgOpen source ↗. Frameshifting is best known as a regulator of viral gene expression, while its physiological relevance in mammals has remained poorly understood. The authors used the effect to build a synthetic gene circuit and tested it in cancer cell lines and in mouse models of colorectal and pancreatic cancer.
Codon-pair frameshifting in cancer cells
According to the authors, the recoding arises from ribosomal pausing associated with tRNA and amino acid availability doi.org
doi.orgdoi.orgOpen source ↗. It is amplified by impaired ribosome quality control and by sustained phosphorylation of ribosomal protein S6
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The authors describe codon-pair-specific frameshifting as an intrinsic state of translational dysregulation. They report that it is prevalent across cancer cells and reshapes protein synthesis doi.org
doi.orgdoi.orgOpen source ↗. The work links this state to earlier studies of aberrant translation in tumours.
FAST circuit and results in mice
To take advantage of this state, the researchers engineered a frameshifting-activated synthetic therapeutic circuit, FAST. It conditionally expresses gasdermin D, an effector of pyroptosis, a form of inflammatory cell death doi.org
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The authors report that FAST is activated across diverse cancer cell types and induces potent, selective pyroptosis. They detected no toxicity in normal tissues doi.org
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As a proof of concept, they delivered FAST systemically with an AAV9 vector in mouse models of colorectal and pancreatic cancer. Treatment produced pronounced tumour regression and robust immune activation. It also showed synergistic effects with immune checkpoint blockade doi.org
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The results come from cell cultures and mice. The authors conclude that codon-pair-dependent frameshifting is a feature of translational dysregulation in cancer cells and that translation-coupled gene circuits can serve as a strategy for cancer-selective therapy doi.org
doi.orgdoi.orgOpen source ↗. The material contains no data on human patients.
