In Situ STING-Activating Nanovaccination with TIGIT Blockade for Enhanced Immunotherapy of Anti-PD-1-Resistant Tumors
Beibei Zhang1,2, Juan Zhang1, Yaqiong Li1
1Department of Ultrasound, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, 450003, Zhengzhou, China.
Abstract:
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.
Insights
This study introduces a novel nanoplatform that blocks the TIGIT checkpoint and activates STING signaling to enhance antitumor immunity. This approach shows promise for overcoming resistance to cancer immunotherapies and preventing tumor recurrence.
Area of Science:
- Biomedical Engineering
- Cancer Immunology
- Nanomedicine
Background:
- Programmed cell death protein 1/PD ligand 1 (PD-1/PD-L1) inhibitors are effective cancer immunotherapies but face challenges with low response rates and resistance.
- Alternative immune checkpoints, like T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), contribute to treatment failure.
- Inefficient T-cell stimulation further limits the efficacy of current cancer treatments.
Purpose of the Study:
- To develop a biomimetic nanoplatform for simultaneous TIGIT checkpoint blockade and stimulator of interferon genes (STING) pathway activation.
- To enhance antitumor immunity and overcome resistance to existing cancer immunotherapies.
- To establish a novel strategy for in situ cancer vaccination.
Main Methods:
- Engineered a nanoplatform by fusing red blood cell membranes with liposomes containing cascade-activating chemoagents (β-lapachone and tirapazamine).
- Incorporated a detachable TIGIT blocking peptide (RTLT) onto the nanoplatform.
- Investigated the nanoplatform's efficacy in reversing T-cell exhaustion, activating STING signaling, and inhibiting tumor growth, metastasis, and recurrence in vivo.
Main Results:
- The nanoplatform successfully blocked the TIGIT checkpoint and activated STING signaling in the tumor microenvironment.
- Released chemotherapeutic agents induced DNA damage, leading to robust in situ STING activation and enhanced immune response.
- The RTLT-nanoplatform demonstrated inhibition of anti-PD-1-resistant tumor growth and prevention of metastasis and recurrence by inducing antigen-specific immune memory.
Conclusions:
- The developed biomimetic nanoplatform offers a dual-action strategy to overcome cancer immunotherapy resistance.
- Simultaneous TIGIT blockade and STING activation represent a promising approach for enhancing antitumor immunity.
- This nanoplatform provides a potential platform for in situ cancer vaccination and long-term immune memory.
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