MN42-81: A novel PD-L1-targeted immunomodulatory cisplatin prodrug for highly efficient synergistic chemo-immunotherapy of cancer.

Cisplatin is a widely used chemotherapeutic agent, but its clinical application is limited by toxic side effects and an "immunological paradox": while chemotherapy kills tumor cells, it also induces upregulation of PD-L1, leading to immune escape. To address this, this study designed a PD-L1-targeted cisplatin prodrug, MN42-81, which can co-release cisplatin and a PD-L1 inhibitor within tumor cells, achieving synergistic antitumor effects through combined chemotherapy and immunomodulation. In vitro experiments demonstrated that MN42-81 exhibits superior anti-proliferative activity across multiple cancer cell lines compared to control groups, and it can inhibit cell migration, induce cell cycle arrest, and promote apoptosis, with an apoptosis rate of 59.60%. At the molecular level, this prodrug downregulates PD-L1 and Bcl-2 expression while activating Caspase-3. In a CT26 xenograft model, MN42-81 showed significant tumor suppression at doses ranging from 2.5 to 10 mg/kg, with no obvious systemic toxicity observed at low to medium doses. This study provides a feasible prodrug design strategy to overcome the limitations of cisplatin therapy.