Nanotherapeutic System with Effective Microwave Sensitization and Pyroptosis Programming Enable Synergistic Microwave-Immunotherapy in Bladder Cancer

Abstract

Currently, the prognosis for patients with advanced bladder cancer remains poor, with only a minority being sensitive to immune checkpoint inhibitors. There is a need to develop additional treatment strategies. Microwave therapy, as a promising approach for some inoperable tumors, still faces challenges such as limited efficacy and high recurrence rates. Additionally, the cell damage and necrosis induced by conventional microwave treatment only act as weak immunostimulatory factors for antitumor immunity, failing to activate effective antitumor immune responses. Recent discoveries have shown that inducing pyroptosis can provide a good opportunity for enhancing systemic immune responses and alleviating immune suppression in cancer therapy. Here, we have developed Mn-ZrMOF@DAC, a microwave-sensitized nanoparticle loaded with the DNA methylation inhibitor decitabine. The Mn-ZrMOF@DAC can enhance the effect of microwave thermal therapy and generate reactive oxygen species under microwave irradiation, causing thermal and oxidative damage to cancer cells. Furthermore, there was an important up-regulation of the key pyroptosis protein GSDME, with a marked increase in pyroptotic cell numbers. In vivo experiments demonstrated that mice injected with Mn-ZrMOF@DAC nanoparticles followed by microwave radiation treatment exhibited potent antitumor effects and enhanced the efficacy of anti-PD-1 therapy. This therapy not only enhanced the efficacy of microwave treatment, exhibiting significant antitumor effects, but also activated antitumor immunity by inducing pyroptosis, thus enhancing the efficacy of immunotherapy for bladder cancer. It holds promise for providing new avenues in the treatment of bladder cancer.