Engineered nanogels simultaneously implement HDAC inhibition and chemotherapy to boost antitumor immunity via pyroptosis

Regulating the immunosuppressive status of the tumor immune microenvironment to overcome immune checkpoint blockade (ICB) resistance still meets many obstacles. Pyroptosis is always accompanied by the release of inflammatory cytokines to recruit immune cells, which shows great potential in tumor immune therapy. Epigenetic treatments, especially histone deacetylase inhibitors (HDACIs), may play a decisive role in pyroptosis induction after our verification. Moreover, the strong effect of HDACIs on improving the tumor microenvironment could enhance the immunocompetence of the immune cells recruited by pyroptosis. Therefore, we rationally designed an effective tumor microenvironment-responsive prodrug-based nanogel LAQ824-Doxorubicin Nanoparticles (LD NPs) combining HDACI LAQ824 and the pyroptosis-inducing chemotherapeutic doxorubicin (DOX) to reshape tumor immunity via pyroptosis. As a result, LD NPs exhibited synergistic pyroptosis-inducing capacity and great biosafety in vivo. LD NPs effectively increased the numbers of tumor infiltrating cytotoxic CD8+ T cells and CD8+ memory T cells via the maturation of dendritic cells (DCs), and immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were simultaneously reduced. Furthermore, LD NPs could significantly improve the response rate and survival period of anti-PD-1 therapy. Thus, LD NPs may provide potential prospect for improving tumor microenvironment immunity and reversing ICB therapy resistance in the clinic.