Acceptor Engineering for Optimized ROS Generation Facilitates Reprogramming Macrophages to M1 Phenotype in Photodynamic Immunotherapy

Reprogramming tumor-associated macrophages to an antitumor M1 phenotype by photodynamic therapy (PDT) is a promising strategy to overcome the immunosuppression of tumor microenvironment for boosted cancer immunotherapy. However, it still remains unclear how the reactive oxygen species (ROS) generated from type I and II mechanisms relate to the corresponding macrophage polarization efficacy. In this contribution, we rationally design and synthesize three donor-acceptor structured photosensitizers with aggregation-enhanced ROS generation. Their ROS-generating efficiencies can be adjusted by changing the acceptor, resulting in varied capabilities to activate macrophages. Surprisingly, we discover that the extracellular ROS generated from type I mechanism are mainly responsible for reprogramming the macrophages from a pro-tumor type (M2) to an anti-tumor state (M1).  In vivo  experiments further prove that the AIEgen photosensitizer can trigger photodynamic immunotherapy for effective suppression of the tumor growth in mice with a single PDT treatment, while the therapeutic outcome is significantly abolished in the mice with depleted macrophages. Overall, our strategy highlights the molecular designing guideline of macrophage-activatable photosensitizers and provides new insights into the working principle of macrophage activation in photodynamic immunotherapy.