Outer Membrane Vesicle-Based Nanohybrids Target Tumor-Associated Macrophages to Enhance Trained Immunity-Related Vaccine-Generated Antitumor Activity.

Trained immunity refers to the innate immune system building memory-like features in response to subsequent infections and vaccinations. Compared with classical tumor vaccines, trained immunity-related vaccines (TIrV) are independent of tumor-specific antigens. Bacterial outer membrane vesicles (OMVs) contain an abundance of PAMPs and have the potential to act as TIrV-inducer, but face challenges in endotoxin tolerance, systemic delivery, long-term training, and trained tumor-associated macrophage (TAM)-mediated antitumor phagocytosis. Here, we developed an OMV-based TIrV, OMV nanohybrids (OMV-SIRPα@CaP/GM-CSF) for exerting vaccine-enhanced antitumor activity. In the bone marrow, GM-CSF-assisted OMVs trained bone marrow progenitor cells and monocytes, which were inherited by TAMs. In tumor tissues, SIRPα-Fc-assisted OMVs triggered TAM-mediated phagocytosis. This TIrV can be identified by metabolic and epigenetic rewiring using transposase-accessible chromatin (ATAC) and transcriptome sequencing. Furthermore, we found that the TIrV-mediated antitumor mechanism in MC38 tumor model (TAM-hot & T cell-cold) is trained immunity and activated T cell response, whereas in B16-F10 tumor model (T cell-hot & TAM-cold) is primarily mediated by trained immunity. Our study not only developed and identified OMV-based TIrV, but also investigated the trained immunity signatures and therapeutic mechanisms, providing a basis for further vaccination strategies. This article is protected by copyright. All rights reserved.