Prodrug Celecoxib-Derived Nanoparticles Potentiate the Efficacy of Cancer Immunotherapy by Remodeling the Tumor Microenvironment

Abstract

Cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play crucial roles in promoting tumor growth and facilitating immune evasion within the tumor microenvironment (TME)-functions that limit responses to immunotherapy. Recent research has highlighted the potential of celecoxib (CXB), a potent COX-2 selective inhibitor, for enhancing the effectiveness of immunotherapy by blocking the COX-2/PGE2 axis. However, the clinical application of CXB for cancer treatment is still hindered by its systemic adverse effects and lack of tumor-targeting. Here, to address these limitations, PEGylated prodrug CXB-derived nanoparticles (CXB-NPs) are developed, a nanomedicine designed to improve the tumor delivery of CXB while minimizing its adverse side effects. CXB-NPs demonstrate enhanced tumor accumulation and effectively inhibit tumor growth by improving the immunosuppressive TME in immunocompetent mice, surpassing the performance of parental CXB. Furthermore, when combined with anti-PD-1 antibody (alpha PD-1) immunotherapy, CXB-NPs exhibit superior suppression of CT26 tumor growth compared with alpha PD-1 monotherapy. This combination approach reduces the infiltration of immunosuppressive immune cells while promoting the infiltration and cytotoxicity of CD8+ T cells. The findings indicate that CXB-NPs capable of remodeling the TME provide a new combination therapy strategy for potentiating antitumor efficacy. Cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play crucial roles in promoting tumor growth and facilitating immune evasion within the tumor microenvironment (TME). In this work, the development of PEGylated CXB-based nanoparticles (CXB-NPs) for enhanced tumor accumulation of CXB is reported, which effectively remodels the TME by inhibiting the COX-2/PGE2 axis. Together with aPD-1, CXB-NPs demonstrate synergistic antitumor efficacy against CT26 tumors.image