Department of Ultrasound, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, 450003, Zhengzhou, China.
School of Biological Engineering, Henan University of Technology, 450001, Zhengzhou, China.
Adv Mater. 2023 Jun;35(24):e2300171. doi: 10.1002/adma.202300171. Epub 2023 Apr 28.
Immunotherapies comprising programmed cell death protein 1/PD ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors are effective cancer treatments. However, the low response rate and immunoresistance resulting from alternative immune checkpoint upregulation and inefficient immune stimulation by T cells are problematic. The present report describes a biomimetic nanoplatform that simultaneously blocks the alternative T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) checkpoint and activates the stimulator of interferon genes (STING) signaling pathway in situ for enhanced antitumor immunity. The nanoplatform is engineered by fusing a red blood cell membrane with glutathione-responsive liposome-encapsulated cascade-activating chemoagents (β-lapachone and tirapazamine), and anchoring them with a detachable TIGIT block peptide (named as RTLT). In the tumor environment, the peptide is spatiotemporally released to reverse T-cell exhaustion and restore antitumor immunity. The cascade activation of chemotherapeutic agents causes DNA damage and inhibits the repair of double-stranded DNA, which induces robust in situ STING activation for an efficient immune response. The RTLT inhibits anti-PD-1-resistant tumor growth, and prevents tumor metastasis and recurrence in vivo by inducing antigen-specific immune memory. This biomimetic nanoplatform thus provides a promising strategy for in situ cancer vaccination.
免疫疗法包括程序性细胞死亡蛋白 1/PD 配体 1（PD-1/PD-L1）免疫检查点抑制剂，是有效的癌症治疗方法。然而，由于替代免疫检查点的上调和 T 细胞的免疫刺激效率低下，导致反应率低和免疫抵抗，这是一个问题。本报告描述了一种仿生纳米平台，该平台同时阻断替代 T 细胞免疫球蛋白和免疫受体酪氨酸基抑制基序域（TIGIT）检查点，并在原位激活干扰素基因刺激物（STING）信号通路，以增强抗肿瘤免疫。该纳米平台通过将红细胞膜与谷胱甘肽响应性脂质体包封的级联激活化疗药物（β-拉帕醌和替拉扎胺）融合，并将其与可分离的 TIGIT 阻断肽（命名为 RTLT）锚定来构建。在肿瘤环境中，肽被时空释放以逆转 T 细胞耗竭并恢复抗肿瘤免疫。化疗药物的级联激活导致 DNA 损伤并抑制双链 DNA 的修复，从而诱导有效的免疫反应的原位 STING 激活。RTLT 通过诱导抗原特异性免疫记忆来抑制抗 PD-1 耐药肿瘤的生长，并防止体内肿瘤转移和复发。因此，这种仿生纳米平台为原位癌症疫苗接种提供了一种有前途的策略。
