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Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

ABSTRACT: Nanozymes and cyclic GMP-AMP synthase (cGAS) the stimulator of interferon genes (STING) signaling pathway, as powerful organons, can remodel the tumor microenvironment (TME) to increase efficacy and overcome drug resistance in cancer immunotherapy. Nanozymes have the potential to manipulate the TME by producing reactive oxygen species (ROS), which lead to positive oxidative stress in tumor cells. Cyclic dinucleotide (2',3'-cGAMP), as a second messenger, exists in the TME and can regulate it to achieve antitumor activity. In this work, Co,N-doped carbon dots (CoNCDs) were used as a model nanozyme to evaluate the properties of the anti-tumor mechanism, and effective inhibition of S180 tumor was achieved. Based on CoNCDs' good biocompatibility and therapeutic effect on the tumor, we then introduced the cGAS-STING agonist, and the combination of the CoNCDs and STING agonist significantly inhibited tumor growth, and no significant systemic toxicity was observed. The combined system achieved the enhanced tumor synergistic immunotherapy through TME reprogramming via the peroxidase-like activity of the CoNCDs and cGAS-STING signaling pathway agonist synergistically. Our work provides not only a new effective way to reprogram TME in vivo, but also a promising synergic antitumor therapy strategy.

SUBMITTER: Dong W

PROVIDER: S-EPMC10530945 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

Dong Wenpei W Chen Mengting M Chang Chun C Jiang Tao T Su Li L Chen Changpo C Zhang Guisheng G

International journal of molecular sciences 20230911 18

Nanozymes and cyclic GMP-AMP synthase (cGAS) the stimulator of interferon genes (STING) signaling pathway, as powerful organons, can remodel the tumor microenvironment (TME) to increase efficacy and overcome drug resistance in cancer immunotherapy. Nanozymes have the potential to manipulate the TME by producing reactive oxygen species (ROS), which lead to positive oxidative stress in tumor cells. Cyclic dinucleotide (2',3'-cGAMP), as a second messenger, exists in the TME and can regulate it to a ...[more]

PMID: 37762239

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Project description:BackgroundThe absence of representative Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) cell lines has limited our understanding of the molecular and immunological characteristics of this cancer subtype.MethodsWe reviewed patients with metastatic cholangiocarcinoma at Sun Yat-sen University Cancer Center from January 2015 to August 2023. Among them, 22 patients with EBVaICC and 66 patients with non-EBVaICC who received anti-PD1 treatment were included. Additionally, 2 EBV-positive ICC cell lines, RBE-EBV and HuH28-EBV, were developed through cell-to-cell infection. Stable EBV infection and responsiveness to viral reactivation were confirmed. Transcriptomic and bioinformatics analyses were performed, and in vitro experiments examined the immune effects of EBV-positive ICC. Key immune-related genes and cytokines were validated by reverse transcription quantitative polymerase chain reaction and ELISA in cell lines and patient plasma samples.ResultsIn this study, we found that patients with EBVaICC showed enhanced immune responses and improved overall and progression-free survival compared to patients with non-EBVaICC. We first successfully established and validated 2 EBV-positive ICC cell lines (RBE-EBV and HuH28-EBV). These cell lines were confirmed for stable EBV infection and displayed responsiveness to viral reactivation, making them suitable for future studies. Transcriptomic analyses and in vitro studies revealed that EBV activated the cGAS-STING pathway, resulting in MHC-I upregulation and CXCL10 secretion in ICC cells, which collectively enhanced CD8+ T cell chemotaxis and cytotoxicity. Furthermore, ELISA analysis showed higher plasma levels of CXCL10 and IFN-γ in patients with EBVaICC, suggesting a potential role for EBV in enhancing immunotherapy sensitivity in this subtype.ConclusionsThe established EBV-positive ICC cell lines revealed enhanced immunogenicity driven by cGAS-STING pathway activation, providing valuable models for future research and insights into the mechanisms of improved immunotherapy sensitivity in EBVaICC.

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Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

Publications

Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

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