A cascade-responsive nanoplatform for cyclooxygenase-2 inhibition and inflammation regulation to enhance photoimmunotherapy

Photodynamic immunotherapy (PIT) has emerged as a promising cancer treatment by photo-activating host immune system to eliminate tumor. However, excessive oxidative stress generated during PIT often induces uncontrolled inflammatory responses and activates immunosuppressive pathways to determine the efficacy of PIT. Herein, we developed a cascade responsive nanoplatform (FBC@PTI) to reduce the inflammation level by co-assembly of an indomethacin-based amphiphilic block copolymer and photosensitizer tetrafluorophenyl bacterial chlorophyll (FBC). Under acidic TME conditions, FBC@PTI underwent surface charge reversal to facilitate tumor penetration and cell internalization. Upon 750 nm light irradiation, FBC could not only generate robust reactive oxygen species (ROS) to induce immunogenic cell death (ICD), but also trigger the disassociation of FBC@PTI to release indomethacin, and inhibit cyclooxygenase-2 (COX-2) to reduce inflammatory level. In vivo experiments demonstrated that the released indomethacin can effectively suppress the expression level of COX-2 (61.1%) and PGE₂ (66.5%), and then reduce the inflammatory factor level of TNF-α (25.8%) and IL-6 (74.0%) from macrophages. As a result, immune activity could further elevate to enhance CD4⁺ and CD8⁺ T cell infiltration and reduce Treg accumulation under controllable inflammatory level. This strategy of regulating inflammation in PIT would offer a potential path for improving the efficacy of PIT. STATEMENT OF SIGNIFICANCE: We developed a cascade responsive nanoplatform (FBC@PTI) that integrates photoimmunotherapy with programmable inflammation modulation. Enabled by pH-triggered charge reversal and light-induced ROS generation, this system enhances tumor-targeted delivery, induces immunogenic cell death, and simultaneously releases indomethacin to inhibit COX-2-mediated inflammatory signaling. By coordinating immune activation with precise inflammation regulation, this strategy offers a promising approach to improve the therapeutic efficacy of photoimmunotherapy.