Bremachlorin-Based Photodynamic-Therapy-Induced Effects in Low-Oxygenated Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment

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Photodynamic therapy (PDT) is a minimally invasive treatment whose efficacy is strongly influenced by tumor oxygenation and the tumor microenvironment (TME). Pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia, dense stroma, and immune suppression, limiting therapeutic responsiveness. In this study, we investigated how Bremachlorin-based PDT remodels the TME in two murine PDAC models with distinct immune phenotypes (T-cell–high and T-cell–low) and compared them with the immunogenic MC38 colon carcinoma model. Single-fiber reflectance and fluorescence spectroscopy were used to monitor tumor physiology and photosensitizer dynamics during PDT, while multiplex immunohistochemistry enabled spatial profiling of stromal and immune components post-treatment. PDAC tumors exhibited significantly lower baseline oxygenation than MC38 tumors, which was not substantially improved by reducing the PDT fluence rate from 116 to 50 mW·cm−2. Nevertheless, PDT reduced collagen type I content in both PDAC models, indicating stromal remodeling. Importantly, illumination with a moderate fluence rate of 50 mW·cm−2 significantly increased CD8+ T-cell infiltration and improved the CD8+/neutrophil ratio in T-cell–high PDAC tumors, suggesting a shift toward a less immunosuppressive immune landscape. These findings demonstrate that Bremachlorin-PDT can modulate the PDAC tumor microenvironment and highlight the importance of immune context in shaping PDT outcomes, supporting rational optimization of PDT-based combination therapies.