Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy
Abstract As an essential intracellular immune activation pathway, the cGAS‐STING pathway has attracted broad attention in cancer treatment. However, low bioavailability, nonspecificity, and adverse effects of small molecule STING agonists severely limit their therapeutic efficacy and in vivo applica...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202309583 |
| _version_ | 1797202513818025984 |
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| author | Yumeng Xing Ao Peng Jianhui Yang Zhifei Cheng Yi Yue Feilong Liu Fenghe Li Yang Liu Qi Liu |
| author_facet | Yumeng Xing Ao Peng Jianhui Yang Zhifei Cheng Yi Yue Feilong Liu Fenghe Li Yang Liu Qi Liu |
| author_sort | Yumeng Xing |
| collection | DOAJ |
| description | Abstract As an essential intracellular immune activation pathway, the cGAS‐STING pathway has attracted broad attention in cancer treatment. However, low bioavailability, nonspecificity, and adverse effects of small molecule STING agonists severely limit their therapeutic efficacy and in vivo application. In this study, a peptide‐based STING agonist is first proposed, and KLA is screened out to activate the cGAS‐STING pathway by promoting mitochondrial DNA (mtDNA) leakage. To precisely activate the cGAS‐STING pathway and block the PD‐1/PD‐L1 pathway, a multi‐stimuli activatable peptide nanodrug (MAPN) is developed for the effective delivery of KLA and PD‐L1 antagonist peptide (CVR). With rational design, MAPN achieved the site‐specific release of KLA and CVR in response to multiple endogenous stimuli, simultaneously activating the cGAS‐STING pathway and blocking PD‐1/PD‐L1 pathway, ultimately initiating robust and durable T cell anti‐tumor immunity with a tumor growth inhibition rate of 78% and extending the median survival time of B16F10 tumor‐bearing mice to 40 days. Overall, antimicrobial peptides, which can promote mtDNA leakage through damaging mitochondrial membranes, may be potential alternatives for small molecule STING agonists and giving a new insight for the design of novel STING agonists. Furthermore, MAPN presents a universal delivery platform for the effective synergy of multiple peptides. |
| first_indexed | 2024-04-24T08:04:38Z |
| format | Article |
| id | doaj.art-1cdc9cb93b324b60b60b4d84fbed19db |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T08:04:38Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-1cdc9cb93b324b60b60b4d84fbed19db2024-04-17T12:48:22ZengWileyAdvanced Science2198-38442024-04-011115n/an/a10.1002/advs.202309583Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer ImmunotherapyYumeng Xing0Ao Peng1Jianhui Yang2Zhifei Cheng3Yi Yue4Feilong Liu5Fenghe Li6Yang Liu7Qi Liu8School of Pharmacy Anhui Medical University Hefei 230032 ChinaSchool of Pharmacy Anhui Medical University Hefei 230032 ChinaSchool of Pharmacy Anhui Medical University Hefei 230032 ChinaSchool of Pharmacy Anhui University of Chinese Medicine Hefei 230012 ChinaSchool of Pharmacy Anhui Medical University Hefei 230032 ChinaSchool of Pharmacy Anhui Medical University Hefei 230032 ChinaSchool of Pharmacy Anhui Medical University Hefei 230032 ChinaCollege of Chemistry Nankai University Tianjin 300071 ChinaSchool of Pharmacy Anhui Medical University Hefei 230032 ChinaAbstract As an essential intracellular immune activation pathway, the cGAS‐STING pathway has attracted broad attention in cancer treatment. However, low bioavailability, nonspecificity, and adverse effects of small molecule STING agonists severely limit their therapeutic efficacy and in vivo application. In this study, a peptide‐based STING agonist is first proposed, and KLA is screened out to activate the cGAS‐STING pathway by promoting mitochondrial DNA (mtDNA) leakage. To precisely activate the cGAS‐STING pathway and block the PD‐1/PD‐L1 pathway, a multi‐stimuli activatable peptide nanodrug (MAPN) is developed for the effective delivery of KLA and PD‐L1 antagonist peptide (CVR). With rational design, MAPN achieved the site‐specific release of KLA and CVR in response to multiple endogenous stimuli, simultaneously activating the cGAS‐STING pathway and blocking PD‐1/PD‐L1 pathway, ultimately initiating robust and durable T cell anti‐tumor immunity with a tumor growth inhibition rate of 78% and extending the median survival time of B16F10 tumor‐bearing mice to 40 days. Overall, antimicrobial peptides, which can promote mtDNA leakage through damaging mitochondrial membranes, may be potential alternatives for small molecule STING agonists and giving a new insight for the design of novel STING agonists. Furthermore, MAPN presents a universal delivery platform for the effective synergy of multiple peptides.https://doi.org/10.1002/advs.202309583antimicrobial peptidescancer immunotherapycGAS‐STING activationmulti‐stimuli activatablePD‐1/PD‐L1 blockade |
| spellingShingle | Yumeng Xing Ao Peng Jianhui Yang Zhifei Cheng Yi Yue Feilong Liu Fenghe Li Yang Liu Qi Liu Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy Advanced Science antimicrobial peptides cancer immunotherapy cGAS‐STING activation multi‐stimuli activatable PD‐1/PD‐L1 blockade |
| title | Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy |
| title_full | Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy |
| title_fullStr | Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy |
| title_full_unstemmed | Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy |
| title_short | Precisely Activating cGAS‐STING Pathway with a Novel Peptide‐Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy |
| title_sort | precisely activating cgas sting pathway with a novel peptide based nanoagonist to potentiate immune checkpoint blockade cancer immunotherapy |
| topic | antimicrobial peptides cancer immunotherapy cGAS‐STING activation multi‐stimuli activatable PD‐1/PD‐L1 blockade |
| url | https://doi.org/10.1002/advs.202309583 |
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