Glutathione depletion and photosensitizer activation augments efficacy of tumor photodynamic immunotherapy

Photodynamic therapy (PDT) is a novel and promising clinical therapy, that is proven these years to be able to induce immunogenicity of tumor cells and activate anti-tumor immunity. However, its application is constrained by the upregulated glutathione (GSH) concentration in tumor cells, coupled with aggregation-caused quenching (ACQ) effect which impedes activation of photosensitizers, thereby hindering the production of reactive oxygen species (ROS) and lowering efficacy. Here, we developed a drug delivery system PSSP, containing a poly(disulfide) (PSS) frame with high disulfide content and Pheophorbide a (Ppa) for laser-induced photodynamic immunotherapy. The PSS bond responded well and effectively depleted high GSH content to a certain degree, under high GSH levels in tumor cells. Moreover, Ppa maintained a hydrophobic property and exhibited excellent performance when bonded with albumin in tumor cells. Taken together, our findings indicated that the PSSP drug delivery system circumvented the shortcomings of abundant GSH in tumor cells and ACQ of photosensitizers, effectively activated the photosensitizer, and elicited more powerful PDT effects, thereby inducing more efficient immunogenic cell death (ICD) effect, and consequently strongly activating immunity to eliminate tumor cells.