Gong Liming, Liu Yanhong, Feng Jing, Xiao Congcong, Liu Chenfei, Chen Bohan, Chen Liqing, Jin Mingji, Guan Youyan, Gao Zhonggao, Huang Wei
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
J Nanobiotechnology. 2025 Jun 16;23(1):447. doi: 10.1186/s12951-025-03521-9.
Breast cancer as a "cold" tumor presents an immunosuppressive microenvironment and inferior T-lymphocyte infiltration, leading to poor efficacy of immune checkpoint blockade (ICB) therapies. It is urgent to develop new effective combination treatment strategies. Pyroptosis is an inflammatory form of programmed cell death mediated by Caspase-1/GSDMD pathway, which can cause immunogenic cell death (ICD) and boost the immunogenicity of tumor. In this study, an immune activator (siRNA@HA-ZIF-8) was proposed based on metal-organic framework (ZIF-8) nanosystem carrying Zn and PD-L1 siRNA to improve anti-tumor immunotherapy through evoking pyroptosis combined with immune checkpoint blockade. We found that siRNA@HA-ZIF-8 could disintegrate under low pH and release massive amounts of Zn, leading to elevated intracellular osmolarity and ROS, eventually resulting in pyroptosis. Zn overload-triggered pyroptosis caused ICD effect and promoted the maturation of dendritic cells and infiltration of T-lymphocytes, which reprogramed the immunoecology of tumor from "cold" to "hot" state. Meanwhile, the co-delivered PD-L1 siRNA decreased the expression of PD-L1 protein on the tumor surface, relieving immune evasion and recovering the recognition and killing ability of cytotoxic T-lymphocytes, further boosting the immune response. This research not only confirmed the potential of ZIF-8 intrinsically as an immune activator that induces pyroptosis in combination with encapsulated PD-L1 siRNA-mediated ICB therapy for the first time, but also adequately revealed the immune responses mechanism by multiple techniques. This study will provide new strategies for pyroptosis-mediated treatments for augmented anti-tumor immunotherapy and greatly inspire the further development of immune activators based on Zn overload-triggered pyroptotic pathway.
乳腺癌作为一种“冷”肿瘤,呈现出免疫抑制性微环境和较差的T淋巴细胞浸润,导致免疫检查点阻断(ICB)疗法疗效不佳。开发新的有效联合治疗策略迫在眉睫。细胞焦亡是一种由半胱天冬酶-1/GSDMD途径介导的程序性细胞死亡的炎症形式,可导致免疫原性细胞死亡(ICD)并增强肿瘤的免疫原性。在本研究中,基于负载锌和PD-L1小干扰RNA(siRNA)的金属有机框架(ZIF-8)纳米系统,提出了一种免疫激活剂(siRNA@HA-ZIF-8),以通过引发细胞焦亡并结合免疫检查点阻断来改善抗肿瘤免疫治疗。我们发现siRNA@HA-ZIF-8在低pH下会分解并释放大量锌,导致细胞内渗透压和活性氧升高,最终导致细胞焦亡。锌过载引发的细胞焦亡产生ICD效应,促进树突状细胞成熟和T淋巴细胞浸润,从而将肿瘤的免疫生态从“冷”状态重编程为“热”状态。同时,共同递送的PD-L1 siRNA降低了肿瘤表面PD-L1蛋白的表达,减轻免疫逃逸,恢复细胞毒性T淋巴细胞的识别和杀伤能力,进一步增强免疫反应。本研究不仅首次证实了ZIF-8本身作为一种免疫激活剂的潜力,即与封装的PD-L1 siRNA介导的ICB疗法联合诱导细胞焦亡,还通过多种技术充分揭示了免疫反应机制。这项研究将为细胞焦亡介导的增强抗肿瘤免疫治疗提供新策略,并极大地激发基于锌过载触发的细胞焦亡途径的免疫激活剂的进一步开发。
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