Inhibition of cancer stem cell self-renewal by a platinum(II) complex suppresses metastasis in gastrointestinal cancer

Cancer stem cells (CSCs) drive therapy resistance, metastasis, and relapses in gastrointestinal cancers, highlighting the need for novel strategies to target this subpopulation. Here, we characterize the platinum(II) complex trans-[PtI₂(isopropylamine)₂] (I5) as a potent inhibitor of CSC-associated pathways and functions in gastric and pancreatic cancer models. Transcriptomic and functional analyses reveal that I5 markedly suppresses Hedgehog, NOTCH, and JAK/STAT signaling, leading to reduced expression of pluripotency markers (NANOG, SOX2, OCT3/4), CSC surface antigens (CD133, CXCR4), and diminished tumorosphere formation. I5 also induces mitochondrial dysfunction, oxidative stress, and metabolic impairment in CSC-enriched populations. In vivo, I5 pre-treatment significantly impairs tumor initiation and metastatic potential in xenograft models. Unlike cisplatin, I5 overcomes platinum resistance by targeting core self-renewal and survival mechanisms in CSCs. These findings position I5 as a promising therapeutic.