Synergistic nanoassemblies constructed from a STAT3 inhibitor and a cabazitaxel prodrug with enhanced cancer chemo-immunotherapy

Abstract

Signal transducer and activator of transcription 3 serves as a converging point of multiple oncogenic pathways and is constitutively activated in a variety of cancer cells lines. Stattic, a selective inhibitor of signal transducer and activator of transcription 3, has been explored for targeted cancer therapy and can be applied as an effective adjuvant for conventional therapies to improve therapeutic outcomes. Stattic was co-assembled in a cabazitaxel prodrug nanoparticle to form a nanoassembly and prepare a co-delivery system. Its antitumor and anti-metastasis activity was evaluated in a murine B16F10 melanoma model and H22 tumor footpad model. The resultant nanosystem showed favorable colloidal stability, reduced systemic toxicity, improved pharmacokinetics in vivo, and synergistic activity against tumor growth and metastatic burden. Administration of the NPs reduced the percentages of tumor-infiltrating Tregs, myeloid-derived suppressor cells and M2 macrophages, whereas elevated CD8+ T cell infiltration, thereby converting the immunologically cold tumors to immunogenic hot tumors and eliciting strong antitumor immunity. Furthermore, by remodeling the tumor microenvironment, stattic synergized with the taxane-based cabazitaxel drug to enhance drug sensitivity. The intrinsically biodegradable, well-tolerated, and systemically injectable immunostimulatory nanomedicine requires further investigation as a chemo-immunotherapy for the treatment of many types of aggressive cancer.