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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. © 2023 Wiley-VCH GmbH.

Citation

Beibei Zhang, Juan Zhang, Yaqiong Li, Na Li, Yuzhou Wang, Ru Jang, Xiaoxia Xu, Ruifang Li, Zhenzhen Chen, Shaobo Duan, Yongchao Wang, Lianzhong Zhang. In Situ STING-Activating Nanovaccination with TIGIT Blockade for Enhanced Immunotherapy of Anti-PD-1-Resistant Tumors. Advanced materials (Deerfield Beach, Fla.). 2023 Jun;35(24):e2300171

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PMID: 37053496

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