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.
Academy of Advanced Interdisciplinary Research, Xidian University, Xi'an, Shaanxi, 710071, China.
Theranostics. 2023 Mar 5;13(5):1571-1583. doi: 10.7150/thno.79945. eCollection 2023.
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. 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 and . 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. 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.
焦亡的时空控制对癌症免疫治疗有深远的影响。由于超声（US）具有精确的时空控制和减少副作用的特点，声动力学治疗（SDT）有望成为一种有前途的激活焦亡的手段。此外，由于细胞外基质（ECM）耗竭导致的淋巴细胞浸润增加，焦亡引发的免疫反应可以被放大。因此，通过重塑肿瘤微环境来开发声动力学-免疫调节策略以放大焦亡介导的肿瘤免疫治疗，从而增强肿瘤免疫治疗，是非常可取的。我们报道了一种基于声敏剂的有效策略，该声敏剂由负载 LY364947 的多孔配位网络（PCN-224）伪装成红细胞（RBC）膜组成，并评估了在焦亡引发的免疫反应中，PCN-224 激活焦亡、胶原耗竭、免疫细胞浸润和适应性免疫反应。声敏剂在 US 照射下产生活性氧（ROS），并启动 caspase-3 凋亡信号通路，这被认为是 GSDME 介导的焦亡的关键上游激活剂。在随后的由焦亡介导的抗肿瘤免疫反应中，LY364947 通过胶原耗竭来松解 ECM 结构，导致 T 淋巴细胞浸润增强，并且在形成免疫记忆的情况下，几乎完全消除了小鼠模型中的肿瘤。我们的研究结果表明，声动力学-免疫调节的焦亡策略具有强大的抗肿瘤免疫疗效，并为焦亡在癌症免疫学中的作用提供了新的见解。
