Carbon monoxide is best known as a poison, but at low doses it has shown an intriguing ability to hinder cancer metastasis. The problem has been delivery: inhaled gas is hard to control, and earlier carbon monoxide-releasing molecules left toxic metal byproducts behind. A preclinical study in Advanced Science, led by Nancy Du at Weill Cornell Medicine with chemist Binghe Wang of Georgia State University, reports a metal-free prodrug, CO-116, that solves both problems.
Administered intravenously to mice with pancreatic or triple-negative breast cancer, CO-116 remained inactive until converted in the body, then released small, controlled amounts of carbon monoxide. The compound significantly reduced the growth of metastatic tumours in the liver and lungs, with no reported toxicity, weight loss or behavioural changes. Strikingly, smaller doses given more often outperformed a single larger weekly dose of the same total amount, suggesting timing and frequency matter more than quantity.
Mechanistically, CO-116 lowered levels of HRG1, a protein that helps cancer cells import heme, disrupting a signalling pathway that drives cell migration. Raising HRG1 made cells more aggressive; lowering it slowed metastatic growth in both cancer models, marking the protein as a possible therapeutic target and biomarker. Because metastasis often strikes after surgery and chemotherapy appear successful, the authors see such compounds as candidates for adjuvant therapy to reduce recurrence.