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

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 (αPD‐1) immunotherapy, CXB‐NPs exhibit superior suppression of CT26 tumor growth compared with αPD‐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.