Formulation-controlled redaporfin cellular-targeted photodynamic therapy sensitizes tumors to PD-1/PD-L1 blockade via immunogenic cell death

Redaporfin is a clinically advanced photosensitizer developed for vascular-targeted photodynamic therapy (V-PDT), yet its therapeutic utility under long drug-to-light interval, cellular-targeted PDT (C-PDT), remains limited despite substantial tumor exposure. Here, we show that formulation-dependent control of redaporfin photochemistry and ER-associated intracellular localization can convert otherwise non-curative C-PDT into an effective partner for immune checkpoint blockade. Encapsulation in Pluronic®-based micelles prolonged the redaporfin triplet-state lifetime over sevenfold relative to ethanol and over twentyfold relative to a non-micellar aqueous environment, while preserving oxygen accessibility. Direct comparison with Pluronic® F127 demonstrated carrier-specific effects: despite greater cell-free ROS generation, F127 showed lower encapsulation efficiency, poorer storage stability, and inferior intracellular ROS generation and phototoxicity. P123 enhanced ER-associated redaporfin accumulation at 24 h and amplified an ICD phenotype, evidenced by increased calreticulin exposure and HMGB1 release; P123-mediated C-PDT also activated macrophages with an M1-like marker profile and induced adaptive PD-L1 upregulation in surviving CT26 cells. In vivo fluorescence imaging confirmed rapid tumor accumulation and sustained retention of redaporfin/P123 at 24 h. Whereas C-PDT alone and α-PD-L1 monotherapy were non-curative, combination with PD-1 and/or PD-L1 blockade produced durable complete responses in up to 50% of mice. All complete responders remained tumor-free during 120-day follow-up, and dual blockade conferred protection against CT26 rechallenge, providing functional evidence of long-term antitumor immune memory. These findings establish formulation-driven control of intracellular photochemistry and subcellular localization as an underappreciated determinant of PDT-mediated anticancer immunity and provide a translational strategy for repurposing a clinically advanced V-PDT photosensitizer for durable photodynamic immunotherapy.