Jennifer Grandis and colleagues have reported a Phase 0, first-in-human trial of a signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide. The decoy was injected directly into head and neck squamous cell carcinomas (HNSCCs) while patients were under anaesthesia ahead of resection of the tumour. Levels of STAT3-target genes were reduced in the injected tumours compared with saline controls. A chemically modified cyclic STAT3 decoy, which is more stable and can be injected intravenously, showed anticancer activity and inhibition of STAT3-target genes in mice.