A Metal‐Free Carbon Monoxide Prodrug Suppresses Metastasis of Pancreatic and Breast Cancer

ABSTRACT Metastatic recurrence is the principal cause of cancer mortality. Pancreatic ductal adenocarcinoma (PDAC) and triple‐negative breast cancer (TNBC) recur frequently after apparently curative therapy. Carbon monoxide (CO) is an endogenously produced signaling molecule with cytoprotective properties, but clinical use of CO gas is constrained by safety and dose‐control challenges. Here, a metal‐free CO prodrug ( CO‐116 ) suppresses metastatic progression in vivo. In experimental models of PDAC and TNBC, CO‐116 reduces metastatic burden without evidence of overt toxicity while maintaining carboxyhemoglobin within physiological ranges. At an equivalent total weekly dose, dividing the dose into more frequent, lower administrations achieves greater efficacy than a single weekly dose, indicating schedule dependence. Mechanistically, CO‐116 downregulates the heme importer HRG1 and attenuates a downstream CYP1B1–SP1 program; gain‐ and loss‐of‐function studies establish HRG1 as a functional mediator of metastatic progression and CO responsiveness. An independent cohort using a distinct metal‐free scaffold ( CO‐103 ) likewise reduces metastasis in PDAC, supporting a scaffold‐independent class effect. These findings establish a mechanistically anchored, non‐inhaled CO strategy to suppress metastasis and motivate adjuvant development focused on schedule optimization and biomarker‐guided dosing.