Njatcha C, Farooqui M, Almotlak AA, et al. - Given an overactive STAT3 pathway is often seen in non–small cell lung cancer, researchers investigated if STAT3 can be downmodulated to delay or avert lung cancer development that results from an environmental exposure. Mice who were previously exposed to the tobacco carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were then treated with a circular oligonucleotide STAT3 decoy (CS3D). The intermittent course of CS3D resulted in reduction in the occurrence of airway preneoplasias by 42% at 1 week after treatment, decrease in the advancement of preneoplasia to adenomas by 54% at 8 weeks after treatment, and decrease in the size and number of resulting lung tumors by 49.7% and 29.5%, respectively, at 20 weeks following treatment. No toxicity was evident. Based on the findings, it was concluded that a decoy molecule-induced downmodulation of STAT3 activity resulted in both decreased oncogenic signaling in the airway epithelium and favored a lung microenvironment with decreased immunosuppression.