Huo Linlin, Zhu Shiqi, Li Muyao, Tan Mingya, Fan Mengke, Zhao Jiayi, Zeng Jie, Liu Meiling, Liu Kunyan, Tong Chao, Zhao Zhenghuan
College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
College of Life Sciences and Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
Adv Sci (Weinh). 2025 Jan;12(3):e2407713. doi: 10.1002/advs.202407713. Epub 2024 Nov 27.
Pyroptosis inducer, a powerful anti-tumor agent that causes obvious programmed cell death and immune stimulation, has been challenged to trigger specific pyroptotic tumor cell death while keeping pyroptosis silence in normal cells. Here, an intelligent inducer is reported that acts as a reactive oxygen species (ROS) scavenger in normal cells to keep pyroptosis silence, while serving as ROS generator to induce obvious pyroptotic tumor cells death dependent on high hydrogen peroxide levels and near-infrared laser irradiation. This switchable activity ensures this inducer to precisely kill the tumor cells with augmented immunogenicity while causing minimal damage to normal cells. Moreover, the catalase-like activity endows this inducer to overcome limitation of tumor hypoxia on ROS generation and show significant pyroptosis activation, further initiating the immune response to inhibit the tumor metastases in vivo. This study provides valuable insights into design new pyroptosis inducer with controllable pyroptosis activity to specifically induce programmed tumor cell pyroptosis for precise and augmented tumor therapy with minimal side effects.
焦亡诱导剂是一种强大的抗肿瘤药物，可导致明显的程序性细胞死亡和免疫刺激，但要在正常细胞中保持焦亡沉默的同时触发特定的焦亡性肿瘤细胞死亡一直面临挑战。在此，报道了一种智能诱导剂，它在正常细胞中作为活性氧（ROS）清除剂以保持焦亡沉默，而在依赖高过氧化氢水平和近红外激光照射的情况下作为ROS生成剂诱导明显的焦亡性肿瘤细胞死亡。这种可切换的活性确保该诱导剂能精确杀死具有增强免疫原性的肿瘤细胞，同时对正常细胞造成最小的损害。此外，类过氧化氢酶活性使该诱导剂能够克服肿瘤缺氧对ROS生成的限制，并显示出显著的焦亡激活，进一步启动免疫反应以抑制体内肿瘤转移。这项研究为设计具有可控焦亡活性的新型焦亡诱导剂提供了有价值的见解，以特异性诱导程序性肿瘤细胞焦亡，实现精确且增强的肿瘤治疗，同时副作用最小。
