Converting Immune Cold into Hot by Biosynthetic Functional Vesicles to Boost Systematic Antitumor Immunity

Summary Immune cold tumor characterized by low immunogenicity, insufficient and exhausted tumor-infiltrating lymphocytes and immunosuppressive microenvironment is the main bottleneck responsible for low patient response rate of immune checkpoint blockade. Here, we developed biosynthetic functional vesicles (BFVs) to convert immune cold into hot through overcome hypoxia, induce immunogenic cell death and immune checkpoint inhibition. The BFVs presents PD1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface, while loads catalase into its inner core. The TRAIL can specifically induce immunogenic death of cancer cells to initiate immune response, which is further synergistically strengthened by blocking PD1/PDL1 checkpoint signal through ectogenic PD1 proteins on BFVs. The catalase can produce O2 to overcome tumor hypoxia, in turn to increase infiltration of effector T cells in tumor. The BFVs elicits robust and systematic antitumor immunity, as demonstrated by significant regression of tumor growth, prevention of abscopal tumors and excellent inhibition of lung metastasis.