Inflammation-Driven Nanohitchhiker Enhances Postoperative Immunotherapy by Alleviating Prostaglandin E2-Mediated Immunosuppression.

Abstract

Inflammation contributes to the immunosuppressive microenvironment and leads to the recurrence of surgically resected tumors. The COX-2/PGE2 axis is considered a key player in shaping the immunosuppression microenvironment. However, targeted modulation of the postoperative tumor microenvironment is challenging. To specifically curb the inflammation and alleviate immunosuppression, here, we developed a PGE2 inhibitor celecoxib (CXB)-loaded bionic nanoparticle (CP@CM) coated with activated murine vascular endothelial cell (C166 cells) membrane to target postoperative melanoma and inhibit its recurrence. CP@CM adhered to inflammatory white blood cells (WBCs) through the adhesion molecules, including ICAM-1, VCAM-1, E-selectin, and P-selection, expressed on the surface of C166 cells. Leveraging the natural tropism of the WBC to the inflammatory postoperative tumor site, CP@CM efficiently targeted postoperative tumors. In melanoma postoperative recurrence models, CXB significantly reduced PGE2 secretion and the recruitment of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) by inhibiting the activity of COX-2. This was followed by an increase in the infiltration of CD8+ T cells and CD4+ T cells in tumor tissues. Additionally, the immune responses were further enhanced by combining a PD-L1 monoclonal antibody. Ultimately, this immunotherapeutic strategy reversed the tumor immunosuppressive microenvironment and inhibited tumor recurrence, demonstrating a promising potential for postoperative immunotherapy for melanoma.