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

Abstract 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, an OMV‐based TIrV is developed, OMV nanohybrids (OMV‐SIRPα@CaP/GM‐CSF) for exerting vaccine‐enhanced antitumor activity. In the bone marrow, GM‐CSF‐assisted OMVs train bone marrow progenitor cells and monocytes, which are inherited by TAMs. In tumor tissues, SIRPα‐Fc‐assisted OMVs trigger TAM‐mediated phagocytosis. This TIrV can be identified by metabolic and epigenetic rewiring using transposase‐accessible chromatin (ATAC) and transcriptome sequencing. Furthermore, it is found that the TIrV‐mediated antitumor mechanism in the MC38 tumor model (TAM‐hot and T cell‐cold) is trained immunity and activated T cell response, whereas in the B16‐F10 tumor model (T cell‐hot and TAM‐cold) is primarily mediated by trained immunity. This study not only develops and identifies OMV‐based TIrV, but also investigates the trained immunity signatures and therapeutic mechanisms, providing a basis for further vaccination strategies.