Manganese-coordinated nanoparticles loaded with CHK1 inhibitor dually activate cGAS-STING pathway and enhance efficacy of immune checkpoint therapy.

Abstract

Notable advancements have been made in utilizing immune checkpoint blockade (ICB) for the treatment of various cancers. However, the overall response rates and therapeutic effectiveness remain unsatisfactory. One cause is the inadequate immune environment characterized by poor T cell infiltration in tumors. To address these limitations, enhancing immune infiltration is crucial for optimizing the therapeutic efficacy of ICB. Activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for initiating immune response and has become a potential target for developing combination therapies with ICB. In this study, we designed and fabricated manganese-containing nanoparticles loaded with the CHK1 inhibitor PF477736, which were subsequently encapsulated with macrophage membrane (PF/MMSN@MPM). This innovative design achieved excellent tumor targeting and demonstrated potent antitumor effects. The combination therapy dually amplified the cGAS-STING pathway, causing a cascade of enhanced therapeutic effects against tumors. Furthermore, single-cell mass cytometry (CyTOF) analysis revealed that PF/MMSN@MPM enhanced the activation and infiltration of immune cells. Moreover, the combination of PF/MMSN@MPM with anti-PD-1 (αPD-1) exhibited a stronger therapeutic effect compared to αPD-1 alone. PF/MMSN@MPM precisely and synergistically activated the cGAS-STING pathway, significantly improving therapeutic efficacy of ICB, and offering promising potential for tumor therapy.