Immunological Conversion of Solid Tumors Using an Outer Membrane Vesicle Based Checkpoint Nanoinhibitor for Cancer Immunotherapy.

Abstract

Immune checkpoint blockade therapy has achieved clinical success, yet its efficacy is often limited by a dysfunctional tumor microenvironment. Crucially, the impairment of local innate immune cells directly drives the paucity and dysfunctionality of tumor-specific T cells. To address these issues, this study developed a nanoscale immune checkpoint modulator based on bacterial outer membrane vesicles (OMVs), in which a PD-L1 blockade peptide ^DPPA-1 is conjugated onto the OMV surface (OMV-^DPPA-1), with the outer surface coated with a polyethylene glycol (PEG) layer containing a legumain-responsive substrate to form PEG-OMV-^DPPA-1. The modification of PEG not only effectively reduces the immunogenicity of OMV-^DPPA-1, thereby bolstering the safety profile of its intravenous deployment and enhancing tumor targeting, but also enables enzyme-triggered controlled release of OMV-^DPPA-1. In tumor-bearing mice, PEG-OMV-^DPPA-1 not only recruits innate immune cells to alleviate the tumor immune-suppressive microenvironment, transforming immunologically "cold" tumors into "hot" tumors, but also precisely blocks immune checkpoints in the tumor microenvironment, protecting tumor-infiltrating T cells from exhausting. In conclusion, this work illuminates the vast potential of OMVs as an effective immunomodulator that can comprehensively regulate the tumor immune microenvironment to enhance cancer immunotherapy.