Remodeling the Tumor Microenvironment: An Emerging Paradigm for Reinvigorating Immunologically Cold Tumors and Advancing Cancer Immunotherapy.

The treatment of solid tumors often faces significant hurdles. These include inefficient drug delivery due to a lack of specific targets and difficulties in penetrating tumors, as well as inadequate immune activation exacerbated by immunosuppressive tumor microenvironments. This study introduces a biomimetic system that employs a fusion membrane (FM) composed of hyaluronidase-decorated bacterial-derived outer membrane vesicles (OMVs) and PD-L1 knockout cancer-derived cell membranes (CCMs). By leveraging the affinity of the OMVs for neutrophils, the FMs can efficiently navigate to tumor sites. The hyaluronidase decoration further overcomes the fibrotic matrix barrier, facilitating the infiltration of immune cells and therapeutic agents. Meanwhile, the genetically edited CCMs not only ensure precise homologous tumor targeting but also minimize the introduction of exogenous immunosuppressive factors. Each component of the FM provides an abundance of antigens, amplifying immune enhancement and addressing the issue of inadequate immune responses. In multiple tumor models, our results demonstrated that FM system exhibited superior tumor targeting, penetration, and immune activation. When combined with chemotherapy and immunotherapy, it led to significant tumor volume reduction and survival benefits. This advanced biomimetic platform integrates precise targeting, efficient drug delivery, and potent immune stimulation, offering a promising approach for solid tumor treatment.