Whole-course Taming of Tumor-associated Macrophages from Central to Peripheral using Engineered Outer Membrane Vesicle Nanohybrids for Improved Immunotherapy [part 2: ATAC-seq]

Only regulation of tumor-associated macrophages (TAMs) in tumor microenvironment (TME) is always insufficient to achieve satisfactory clinical outcome, and training of central progenitor cells of TAMs in bone marrow is a potential approach. To achieve the whole-course taming of TAMs from central to peripheral, we developed nanohybrids containing bacterial outer membrane vesicle (OMV), GM-CSF and SIRPα-Fc fusion protein, which were coated with calcium phosphate (CaP) shell. The surface CaP coating endowed nanohybrids with safe circulation, allowing them to reach both bone marrow and TME. In bone marrow, OMV and GM-CSF together induced trained immunity of central progenitor cells, indicating by transcriptional alterations and epigenetic remodeling, which was inherited to peripheral TAMs. In peripheral TME, OMV and SIRPα-Fc triggered M1-like TAM phagocytosis with subsequent CD8+ T cell activation.