Cancer-selective gene circuits via intrinsic ribosomal frameshifting.

Codon-pair-specific -1 ribosomal frameshifting is preferentially efficient in cancer cells, driven by translational dysregulation linked to tRNA/amino-acid availability and S6 phosphorylation.

• Why it matters: Frameshifting is well characterized in viruses, but its physiological relevance in mammals and its potential for cancer-selective control of protein expression were unclear.
• What they did: The study identified codon pairs that trigger -1 frameshifting in cancer cells, attributing the effect to ribosomal pausing, impaired quality control, and sustained phosphorylation of ribosomal protein S6.
• The result: Using this frameshifting-permissive state, the FAST circuit conditionally expressed gasdermin D to induce selective pyroptosis in diverse cancer cell types and produced pronounced tumour regression with immune activation after systemic AAV9 delivery in mouse models.

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