Pyroptosis induction synergized with IDO inhibition of ternary biomedicine for photodynamic activated tumor immunotherapy

Abstract

The development of immunotherapy is seriously limited by the insufficient tumor immunogenicity and immunosuppressive microenvironment. Pyroptosis is a new form of immunogenic cell death (ICD) associated with the gasdermin protein family, which has received increasing attention as a promising approach to activate antitumor immunity. Herein, we construct a ternary biomedicine (CNS) based on the self-assembly of photosensitizer chlorine e6 (Ce6), NLG919 (NLG) and simvastatin (Sim), which has a fairly high drug content, good stability and uniform morphology. Interestingly, the photodynamic therapy of CNS can generate reactive oxygen species (ROS) to induce intracellular oxidative stress, activating NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/Caspase-1 (Cas-1)/gasdermin D N-terminal domain (GSDMD-N) dependent pyroptosis. Further, Sim-mediated NLRP3 upregulation will also promote cell pyroptosis to activate ICD and stimulate immune responses. Benefiting from NLG-induced indoleamine 2,3-dioxygenase (IDO) inhibition, CNS is capable of improving the immunosuppressive microenvironment to enhance immunotherapy. Consequently, the pyroptosis induction synergized with IDO inhibition of CNS exhibits excellent antitumor immune activities, as evidenced by enhancing DCs maturation and effector memory T cells frequency, which significantly inhibit tumor growth and metastasis. This proposal of self-delivery ternary nanomedicine might open a new window to construct drug delivery systems for pyroptosis activated immunotherapy.