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Life sciences · Journal article
Nature Communications · October 23, 2026
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Abstract Nonsense mutations in tumour suppressor genes (TSGs) drive cancer initiation and progression but remain “undruggable” due to formidable challenges in rescuing the functional impairment of heterogeneous truncated proteins with a single agent. Here we observe that suppressor transfer RNAs (sup-tRNAs) can overcome diverse nonsense mutations in TP53, restoring full-length p53 expression and function. Sup-tRNAs enable high-fidelity incorporation of optimal amino acids and can further enhance the transcriptional activity of p53 to suppress tumour cell proliferation. Moreover, we employ a computational model to guide sup-tRNA design by in silico saturation mutagenesis for targeted readthrough of different nonsense-mutant TSGs. Remarkably, sup-tRNAs produced p53 variants with enhanced activity relative to restored wild-type p53, reducing cancer cell colony area by up to 82%. In two xenograft models harbouring nonsense mutant TP53, we observed up to a 74% reduction in tumour volume after lipid nanoparticle (LNP)-based sup-tRNA treatment, attributed to robust recovery of p53 expression and function. Critically, sup-tRNA monotherapy surpassed nab-paclitaxel chemotherapy in efficacy, and their combination induced near-complete tumour regression (a maximum of 93% reduction in tumour volume) without detectable toxicity in multiple mouse tumour models. Our findings highlight the potential of tRNA-based therapy to provide a promising strategy for rescuing nonsense-mutant TP53.