The DOI matches its Crossref record; 59 of the 60 references it cites were found in a registry or an index.
DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity
Open accessAbstract
Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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“As recent evidence suggests that tumor cell-intrinsic STING is critical to the production of type I IFNs and promotion of CD8+ T cell activation via enhancing the function of APCs,33”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [33]
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377
Self-citationMismatch repair deficiency predicts response of solid tumors to PD-1 blockade
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Self-citationPD-1 blockade induces responses by inhibiting adaptive immune resistance
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TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
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Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
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Next-generation characterization of the Cancer Cell Line Encyclopedia
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Self-citationGenomic correlates of response to CTLA-4 blockade in metastatic melanoma
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1 of the 60 references couldn’t be matched to a known paper.
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Diaz, L. A., Shiu, K., Kim, T., Jensen, B. V., Jensen, L. H., Punt, C. J. A., Smith, D. M., García‐Carbonero, R., Benavides, M., Gibbs, P., et al. (2022) · The Lancet Oncology · doi:10.1016/s1470-2045(22)00197-8 · Cited by 993
Self-citationTurning cold tumors hot: from molecular mechanisms to clinical applications
Zhang, J., Huang, D., Saw, P. E., & Song, E. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.04.010 · Cited by 534
Therapeutic targeting of tumour myeloid cells
Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D., & Morton, J. P. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00546-2 · Cited by 305
Targeting the DNA damage response in immuno-oncology: developments and opportunities
Chabanon, R. M., Rouanne, M., Lord, C. J., Soria, J., Pasero, P., & Postel-Vinay, S. C. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00386-6 · Cited by 306
Regulation of cGAS–STING signalling and its diversity of cellular outcomes
Zhang, Z., & Zhang, C. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01112-7 · Cited by 287
Metadata
- Authors
- Lu, C., Guan, J., Lu, S., Jin, Q., Rousseau, B., Lu, T., Stephens, D., Zhang, H., Zhu, J., Yang, M., Ren, Z., Liang, Y., Liu, Z., Han, C., Liu, L., Cao, X., Zhang, A., Qiao, J., Batten, K., Chen, M., Castrillon, D. H., Wang, T., Li, B., Diaz, L. A., Li, G.-M., & Fu, Y.-X.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Li, Guo-Min
- Fu, Yang-Xin
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 39
- Issue
- 1
- Pages
- 96-108.e6
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC9477183
- OpenAlex
- W3112754342
- Cited by
- 285
- References
- 60
- Citations by year
- 2026: 36 · 2025: 51 · 2024: 53 · 2023: 66 · 2022: 46 · 2021: 32
- FWCI
- 13.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Entertainment Industry Foundation
- Amaldi Research Center
- Astellas Pharma US
- Johns Hopkins University
- Merck
- University of Texas Southwestern Medical Center (RP180725)
- Novartis
- Bayer Fund
- Cancer Prevention and Research Institute of Texas (RR150072, RR160101)
- Jounce Therapeutics
- Gilead Sciences
- Servier
- American Association for Cancer Research
- National Institutes of Health (1R01CA245318-01A1, 5P30CA142543)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- mismatch repair deficiency, MLH1, cytosolic DNA sensing, cGAS-STING pathway, interferon-beta, neoantigens, anti-PD-1 therapy, immune checkpoint blockade, tumor immunogenicity, T cell priming, tumor mutational burden, drug resistance, prognostic factors, cancer immunotherapy
- MeSH terms
- MutL Protein Homolog 1, Immune Checkpoint Inhibitors, STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Female, Humans, Membrane Proteins, Neoplasm Transplantation, Neoplasms, Nucleotidyltransferases, Prognosis, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Interferon-beta, Cell Line, Tumor, Mice, DNA Mismatch Repair
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