STING pathway activation with cisplatin polyprodrug nanoparticles for chemo-immunotherapy in ovarian cancer

Cisplatin serves as the cornerstone medication in ovarian cancer (OC) chemotherapy; however, numerous resistance factors exist, resulting in unsatisfactory clinical treatment outcomes. Concurrently, OC frequently establishes an immunosuppressive microenvironment, which further exacerbates the challenges of cisplatin chemotherapy. Hence, it is particularly significant to explore a therapeutic approach capable of overcoming cisplatin resistance while reversing the immunosuppressive microenvironment of OC. Here, we synthesized a novel cisplatin polyprodrug (PTP) containing thioketal units, which self-assembled with a stimulator of interferon genes (STING) small-molecule agonist (SR-717) to form redox-smart-responsive PTP@SR-717 nano- particles (NPs), enabling synergistic chemo-immunotherapy. Specifically, PTP@SR-717 NPs enhanced the antitumor effect of cisplatin through three key mechanisms: (i) Pre-target factors: Enhancing intracellular cisplatin uptake and reducing GSH-mediated detoxification to promote platinum accumulation. (ii) On-target factors: Utilizing molecular damage-associated molecular patterns (DAMPs) triggered by cisplatin to activate the STING pathway, thereby synergistically amplifying the STING-TBK1-IRF3 signaling and efficiently triggering an immune response. (iii) Post-target factors: Combining chemotherapy and immunotherapy to harness the immune system for tumor eradication. In conclusion, this study presents an effective approach to addressing the challenges associated with cisplatin in the clinical treatment of OC.