Imaging-guided COX-2 inhibition synergizes with photodynamic immunogenic cell death to potentiate checkpoint blockade in colon cancer

Abstract

Colon cancer is a highly aggressive malignancy lacking specific therapeutic targets. Here, we present a therapeutic strategy that integrates inflammation-driven nanomedicine-based photodynamic therapy (PDT) with immune checkpoint blockade (ICB), with holds the potential to eradicate primary tumors and suppress metastasis. The VC@HSA nanomedicine comprises verteporfin (VER), a photosensitizer that induces immunogenic cell death (ICD), and celecoxib (CXB), an inhibitor of prostaglandin E₂ (PGE₂), co-encapsulated within human serum albumin (HSA). By inhibiting PDT-induced PGE₂ upregulation, CXB enhances ICD while alleviating PGE₂-mediated immunosuppression in the tumor microenvironment. The combination therapy synergizes with anti-PD-L1 treatment to elicit a robust antitumor immune response, characterized by increased infiltration of cytotoxic T lymphocytes. Importantly, the HSA-based nanomedicine enables efficient tumor-targeted delivery and holds potential for imaging-guided therapy due to the intrinsic fluorescence properties of the incorporated components. This coordinated immune activation effectively inhibits the growth of primary and distant colon tumors within a short-term in vivo treatment cycle. Collectively, our findings elucidate the mechanism underlying the co-administration of VER and CXB, demonstrate the advantages of albumin as a superior drug carrier, and establish the combination of VC@HSA with ICB as a promising therapeutic strategy for colon cancer.