1. Lab of Molecular Imaging and Translational Medicine (MITM), Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University & International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment, Xi'an, Shaanxi, 710126, P. R. China
2. Academy of Advanced Interdisciplinary Research, Xidian University, Xi'an, Shaanxi, 710071, China.
Rationale: Spatiotemporal control of pyroptosis has a profound impact on cancer immunotherapy. Owing to the precise spatiotemporal control and reduction in the side effects of ultrasound (US), sonodynamic therapy (SDT) is expected to be a promising mean to activate pyroptosis. Furthermore, the pyroptosis-initiated immune response can be amplified by enhanced lymphocyte infiltration occurring due to extracellular matrix (ECM) depletion. Therefore, it is highly desirable to develop a sonodynamic-immunomodulatory strategy to amplify pyroptosis-mediated tumor immunotherapy by remodeling of the tumor microenvironment, thereby enhancing tumor immunotherapy.
Methods: We reported a potent strategy based on a sonosensitizer, which is composed of LY364947-loaded porous coordination network (PCN-224) camouflaged with a red blood cell (RBC) membrane and evaluated pyroptosis activation, collagen depletion, immunocyte infiltration, and adaptive immune response during the pyroptosis-initiated immune response in vitro and in vivo.
Results: The sonosensitizer generated reactive oxygen species (ROS) under US irradiation and initiated the caspase-3 apoptotic signaling pathway, which is regarded as the key upstream activator of gasdermin E (GSDME)-mediated pyroptosis. During the subsequent anti-tumor immune response mediated by pyroptosis, LY364947 loosened the ECM structure via collagen depletion, resulting in enhanced T-lymphocyte infiltration and nearly complete eradication of tumors in a mouse model with the formation of immunological memory.
Conclusion: Our findings indicate that sonodynamic-immunomodulatory pyroptotic strategy exhibits robust anti-tumor immune efficacy as well as provides novel insights into the role of pyroptosis in cancer immunology.
Keywords: pyroptosis, gasdermin E, sonodynamic therapy, tumor microenvironment normalization