Isocyanate-Modified Melatplatin(IV) Enhances Antitumor Efficacy via TCF4/COL6A3-Mediated Extracellular Matrix Remodeling and cGAS-STING Pathway Activation in Bladder Cancer.

Cisplatin (CDDP) chemosensitivity and severe toxicity severely limit its clinical application in muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). To address these unmet clinical needs, we synthesized a series of melatonin-conjugated platinum(IV) prodrugs functionalized with isocyanate chains (compounds 5‒12), and identified MP-12C (compound 11) as the lead candidate with optimal potency and safety. In vitro assays showed that MP-12C exhibited far stronger antiproliferative activity than CDDP and mitomycin C in parental and CDDP-resistant bladder cancer cells. Multiple in vivo models, including subcutaneous xenograft, orthotopic, and chemically induced spontaneous bladder cancer models, were adopted. Both intravenous injection and intravesical instillation of MP-12C achieved robust tumor suppression while reducing toxicity compared to conventional chemotherapeutics. Mechanistically, MP-12C downregulated the TCF4/COL6A3 axis to suppress collagen VI secretion by bladder cancer cells, thereby remodeling the extracellular matrix (ECM) and enhancing the sensitivity of bladder cancer cells to CDDP. MP-12C triggered immunogenic cell death and persistently activated the cGAS-STING pathway, promoting dendritic cell maturation and CD8+ T cell infiltration to remodel the antitumor immune microenvironment. Collectively, MP-12C integrates ECM modulation and immune activation to exert superior anti-bladder cancer efficacy with favorable safety, thus providing a promising platinum(IV) prodrug strategy for NMIBC and MIBC.