cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity
Open accessAbstract
Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.
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Tumor cell-intrinsic STING activity is an important contributor to antitumor immune responses.
“recent studies have provided compelling evidence that tumor cell-intrinsic STING activity is also an important contributor34–36.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [34]
The available passage (article header, no page number) gives the title, which links cGAS/STING to drug-induced tumor immunogenicity, but it contains no findings about tumor cell-intrinsic STING activity or antitumor immune responses. Searches for those terms returned only the header, so the decisive article text appears to be missing from our copy. (LLM, conf=0.70)
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- Authors
- Wang, Z., Chen, J., Hu, J., Zhang, H., Xu, F., He, W., Wang, X., Li, M., Lu, W., Zeng, G., Zhou, P., Huang, P., Chen, S., Li, W., Xia, L.-P., & Xia, X.
- Affiliations
- Sun Yat-sen University Cancer Center (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Sun Yat-sen University (CN)
- Guangdong Laboratory Animals Monitoring Institute (CN)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2019-10-07
- Volume
- 129
- Issue
- 11
- Pages
- 4850-4862
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6819145
- OpenAlex
- W2968331746
- Cited by
- 253
- References
- 10
- Citations by year
- 2026: 23 · 2025: 46 · 2024: 50 · 2023: 42 · 2022: 34 · 2021: 36 · 2020: 20 · 2019: 2
- FWCI
- 9.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81472578, 81773051, 81803005, 81572409, 2018YFC1313300)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- teniposide, topoisomerase II inhibitors, immunogenic cell death, cGAS-STING pathway, HMGB1 release, type I interferon signaling, NF-κB activation, dendritic cell activation, antitumor T-cell responses, anti-PD-1 therapy, chemoimmunotherapy, DNA damage, tumor immunogenicity
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Female, Humans, Immunity, Cellular, Membrane Proteins, Mice, Inbred BALB C, Neoplasm Proteins, Neoplasms, Experimental, Nucleotidyltransferases, T-Lymphocytes, Teniposide, Signal Transduction, Mice, Knockout, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, HEK293 Cells, Topoisomerase II Inhibitors
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