Engineering a photosensitizer nanoplatform for amplified photodynamic immunotherapy via tumor microenvironment modulation

Photosensitizer-based photodynamic therapy (PDT) can not only kill tumor cells by the generated cytotoxic reactive oxygen species (ROS), but also trigger immunogenic cell death (ICD) and activate an immune response for immunotherapy. However, such photodynamic immunotherapy suffers from major obstacles in the tumor microenvironment. The hypoxic microenvironment greatly weakens PDT, while the immunosuppressive tumor microenvironment caused by aberrant tumor blood vessels and indoleamine 2,3-dioxygenase (IDO) leads to a significant reduction in immunotherapy. To overcome these obstacles, herein, an engineered photosensitizer nanoplatform is designed for amplified photodynamic immunotherapy by integrating chlorin e6 (Ce6, a photosensitizer), axitinib (AXT, a tyrosine kinase inhibitor) and dextro-1-methyl tryptophan (1MT, an IDO inhibitor). In our nanoplatform, AXT improves the tumor microenvironment by normalizing tumor blood vessels, which not only promotes PDT by reducing the level of hypoxia of the tumor microenvironment, but also promotes immunotherapy through facilitating infiltration of immune effector cells into the tumor and reversing the immunosuppressive effect of vascular endothelial growth factor (VEGF). Moreover, 1MT effectively inhibits the activity of IDO, further reducing the immunosuppressive nature of the tumor microenvironment. Therefore, this nanoplatform demonstrates an amplified photodynamic immunotherapy via tumor microenvironment modulation, exhibiting outstanding therapeutic efficacy against tumor growth and metastasis with negligible side toxicity. The current concept of engineering photosensitizer nanoplatforms for overcoming photodynamic immunotherapy obstacles provides a promising strategy against tumors.