A Microenvironment Dual-Responsive Nano-Drug Equipped with PD-L1 Blocking Peptide Triggers Immunogenic Pyroptosis for Prostate Cancer Self-Synergistic Immunotherapy

Induction of immunogenic cell death (ICD) in tumor combined with immune checkpoint blockade (ICB) therapy is widely developed to improve the efficacy of cancer immunotherapy. However, the current ICD induced based on apoptosis, i.e., immunogenic apoptosis, is often restricted in immunogenicity owing to the inflammatory quenching that occurs early in apoptosis. Recently, pyroptosis is demonstrated to be a more efficient ICD form, i.e., immunogenic pyroptosis. The cell contents released during pyroptosis can powerfully activate tumor immunogenicity. Herein, first, it is demonstrated that lower doses of epigenetic drug decitabine can increase GSDME expression in prostate cancer (PCa) RM-1 cells and successfully induce an apoptosis-pyroptosis transition after photodynamic therapy (PDT). Subsequently, a microenvironment dual-responsive nano-drug equipped with PD-L1 blocking peptide (TSD@LSN-D) is developed for self-synergistic cancer immunotherapy. The poorly immunogenic RM-1 PCa model confirm that the powerful antitumor immune response evoked by TSD@LSN-D not only can effectively inhibit the primary tumor but also form a long-term immune memory to prevent PCa recurrence and metastasis. To the best of authors' knowledge, this work presents the first concept that promotes the apoptosis-pyroptosis transition after tumor PDT through epigenetic modulation. Furthermore, the powerful combination of immunogenic pyroptosis with ICB opens a new platform for PCa immunotherapy.

Automated summary

The combination of immunogenic cell death induction in tumors and immune checkpoint blockade therapy has been widely developed to enhance the effectiveness of cancer immunotherapy. This study demonstrates that pyroptosis, a form of immunogenic cell death, is more efficient than apoptosis in activating tumor immunogenicity. By using an epigenetic drug decitabine and photodynamic therapy, the apoptosis-pyroptosis transition can be successfully induced in prostate cancer cells. Furthermore, a nano-drug that can respond to the tumor microenvironment and block PD-L1 is developed for self-synergistic cancer immunotherapy, which shows strong antitumor immune response and long-term immune memory in a poorly immunogenic prostate cancer model.