Nanoparticle-Mediated Toll-Like Receptor Activation and Dual Immune Checkpoint Downregulation for Potent Cancer Immunotherapy

Dual blockade of CD47 and PD-L1 immune checkpoints has shown potential in cancer treatment, but its clinical application is hindered by the on-target off-tumor immunotoxicities of monoclonal antibodies. Herein, we report a core–shell nanoparticle, PPA/HG, comprising polyinosinic: polycytidylic acid (PPA) in the core and a cholesterol-conjugated prodrug of 3-(hydroxyolinoyl)glycine (HG) on the shell, for potent cancer immunotherapy. PPA/HG shows a long half-life in the bloodstream to efficiently accumulate in tumors, where PPA/HG rapidly releases HG and PPA. HG inhibits the histone lysine demethylase 3A/c-Myc transduction for effective CD47 and PD-L1 downregulation in cancer cells while PPA activates toll-like receptor 3 in dendritic cells and tumor-associated macrophages to promote dendritic cell maturation and macrophage repolarization. PPA/HG promotes the infiltration and activation of effector T lymphocytes, meanwhile decreasing the population of immunosuppressive regulatory T cells. Systemic administration of PPA/HG significantly inhibits the progression of orthotopic triple-negative breast cancer and pancreatic ductal adenocarcinoma with minimal side effects.