Photodynamic therapy produces enhanced efficacy of antitumor immunotherapy by simultaneously inducing intratumoral release of sorafenib

Abstract

Photodynamic therapy (PDT) can destroy local tumor cells and induce effective antitumor immune responses, and has been applied in the treatment of patients with superficial solid tumors. Numerous systemic side effects of PDT, such as pain and skin photosensitivity, however, limit this therapeutic option. In addition, the immunosuppressive tumor microenvironment has been found to be another critical barrier for the antitumor immunity induced by PDT. Therefore, effectively enhancing the cytotoxicity to tumor cells of low-dose PDT and inhibiting the tumor immunosuppressive tumor microenvironment may be a feasible strategy to overcome these drawbacks of PDT. Here, a sorafenib and chlorin e6 co-loaded reactive oxygen species (ROS)-responsive nanoparticle (NP-sfb/ce6) is developed to improve antitumor responses by intratumoral release of sorafenib at the time of PDT. Under 660-nm laser irradiation, ROS produced by chlorin e6 (ce6) destruct the nanoparticles, resulting in boosted sorafenib cascade release. The rapidly released sorafenib acts synergistically with the low-dose PDT to inhibit tumor growth by inducing strong T cell-dependent local and systemic antitumor immune responses, reprograming the tumor immune microenvironment, and limiting the interaction between cytotoxic CD8⁺ T cells and immunosuppressive cells. This study provides new avenues for cascade-amplifying antitumor effects of photodynamic therapy.

Keywords: Antitumor immunotherapy; Immunosuppressive tumor microenvironment; Intratumoral rapid release; Photodynamic therapy; ROS-responsive nanoparticle; Sorafenib.