STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy
Open accessAbstract
Cancer-associated fibroblasts (CAFs) perform diverse roles and can modulate therapy responses 1. The inflammatory environment within tumours also influences responses to many therapies, including the efficacy of oncolytic viruses 2; however, the role of CAFs in this context remains unclear. Furthermore, little is known about the cell signalling triggered by heterotypic cancer cell-fibroblast contacts and about what activates fibroblasts to express inflammatory mediators 1,3. Here, we show that direct contact between cancer cells and CAFs triggers the expression of a wide range of inflammatory modulators by fibroblasts. This is initiated following transcytosis of cytoplasm from cancer cells into fibroblasts, leading to the activation of STING and IRF3-mediated expression of interferon-β1 and other cytokines. Interferon-β1 then drives interferon-stimulated transcriptional programs in both cancer cells and stromal fibroblasts and ultimately undermines the efficacy of oncolytic viruses, both in vitro and in vivo. Further, targeting IRF3 solely in stromal fibroblasts restores oncolytic herpes simplex virus function.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CAFs can undermine oncolytic viral therapy by upregulating type I interferons and increasing an antiviral response in tumour cells.
“Conversely, CAFs can undermine oncolytic viral therapy by upregulating type I interferons and increasing an antiviral response in tumour cells.132”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [132]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829 · see citing works
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366 · see citing works
A framework for advancing our understanding of cancer-associated fibroblasts
Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., Fearon, D., Greten, F. R., Hingorani, S. R., Hunter, T., et al. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0238-1 · Cited by 3,863 · see citing works
Self-citationIFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Ayers, M., Lunceford, J., Nebozhyn, M., Murphy, E., Loboda, A., Kaufman, D. R., Albright, A., Cheng, J. D., Kang, S. P., Shankaran, V., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci91190 · Cited by 3,788 · see citing works
Mechanisms of type-I- and type-II-interferon-mediated signalling
Platanias, L. C. (2005) · Nature reviews. Immunology · doi:10.1038/nri1604 · Cited by 3,480 · see citing works
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Ishikawa, H., Ma, Z., & Barber, G. N. (2009) · Nature · doi:10.1038/nature08476 · Cited by 2,759 · see citing works
Özdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.005 · Cited by 2,681 · see citing works
Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma
Andtbacka, R. H. I., Kaufman, H. L., Collichio, F. A., AMATRUDA, T. T., Senzer, N. N., Chesney, J. A., Delman, K. A., S̄pitler, L. E., Puzanov, I. J., Agarwala, S. S., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.3377 · Cited by 2,646 · see citing works
Self-citationDistinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590 · see citing works
Puram, S. V., Tirosh, I., Parikh, A. S., Patel, A. P., Yizhak, K., Gillespie, S., Rodman, C., Luo, C. L., Mroz, E. A., Emerick, K. S., et al. (2017) · Cell · doi:10.1016/j.cell.2017.10.044 · Cited by 2,557 · see citing works
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer
Twyman-Saint Victor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., Benci, J. L., Xu, B., Dada, H., Odorizzi, P. M., et al. (2015) · Nature · doi:10.1038/nature14292 · Cited by 2,434 · see citing works
lumi : a pipeline for processing Illumina microarray
Du, P., Kibbe, W. A., & Lin, S. M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn224 · Cited by 2,028 · see citing works
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.011 · Cited by 1,705 · see citing works
Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., & Sahai, E. (2007) · Nature Cell Biology · doi:10.1038/ncb1658 · Cited by 1,589 · see citing works
Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy
Ribas, A., Dummer, R., Puzanov, I., VanderWalde, A., Andtbacka, R. H. I., Michielin, O., Olszanski, A. J., Malvehy, J., Cebon, J., Fernandez, E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.027 · Cited by 1,520 · see citing works
Calvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R. P., Chaudhry, S. I., Harrington, K., Williamson, P., Moeendarbary, E., Charras, G., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2756 · Cited by 1,478 · see citing works
Self-citationSu, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., Wang, M., Luo, M., Xing, Y., Chen, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.009 · Cited by 1,230 · see citing works
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade
Benci, J. L., Xu, B., Qiu, Y., Wu, T. J., Dada, H., Twyman-Saint Victor, C., Cucolo, L., Lee, D. S. M., Pauken, K. E., Huang, A. C., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.022 · Cited by 1,216 · see citing works
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017) · Nature Cell Biology · doi:10.1038/ncb3586 · Cited by 1,196 · see citing works
Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer
Chen, Q., Boire, A., Jin, X., Valiente, M., Er, E. E., Lopez-Soto, A., S. Jacob, L., Patwa, R., Shah, H., Xu, K., et al. (2016) · Nature · doi:10.1038/nature18268 · Cited by 969 · see citing works
Labernadie, A., Kato, T., Brugués, A., Serra‐Picamal, X., Derzsi, S., Arwert, E. N., Weston, A., González-Tarragó, V., Elósegui-Artola, A., Albertazzi, L., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3478 · Cited by 747 · see citing works
Self-citationZamarin, D., Holmgaard, R. B., Subudhi, S. K., Park, J. S., Mansour, M., Palese, P., Merghoub, T., Wolchok, J. D., & Allison, J. P. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008095 · Cited by 711 · see citing works
Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP
Ablasser, A., Schmid-Burgk, J. L., Hemmerling, I., Horvath, G. L., Schmidt, T., Latz, E., & Hornung, V. (2013) · Nature · doi:10.1038/nature12640 · Cited by 649 · see citing works
Marcus, A., Mao, A. J., Lensink-Vasan, M., Wang, L., Vance, R. E., & Raulet, D. H. (2018) · Immunity · doi:10.1016/j.immuni.2018.09.016 · Cited by 609 · see citing works
Oncolytic Viruses in Cancer Treatment
Lawler, S. E., Speranza, M. C., Cho, C., & Chiocca, E. A. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.2064 · Cited by 602 · see citing works
Hirata, E., Girotti, M. R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R., & Sahai, E. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.008 · Cited by 593 · see citing works
Self-citationXia, T., Konno, H., Ahn, J., & Barber, G. N. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.029 · Cited by 589 · see citing works
Benci, J. L., Johnson, L. R., Choa, R., Xu, Y., Qiu, J., Zhou, Z., Xu, B., Ye, D., Nathanson, K. L., June, C. H., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.019 · Cited by 541 · see citing works
Viral evasion of intracellular DNA and RNA sensing
Chan, Y., & Gack, M. U. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.45 · Cited by 451 · see citing works
Tumor Microenvironment and Differential Responses to Therapy
Hirata, E., & Sahai, E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026781 · Cited by 422 · see citing works
Self-citationZhou, Y., Fei, M., Zhang, G., Liang, W., Lin, W., Wu, Y., Piskol, R., Ridgway, J. B., McNamara, E., Huang, H., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.01.014 · Cited by 399 · see citing works
Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited
Verhelst, J., Hulpiau, P., & Saelens, X. (2013) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00024-13 · Cited by 327 · see citing works
miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
Givel, A.-M., Kieffer, Y., Scholer-Dahirel, A., Sirven, P., Cardon, M., Pelon, F., Magagna, I., Gentric, G., Costa, A., Bonneau, C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03348-z · Cited by 295 · see citing works
Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity
Schadt, L., Sparano, C., Schweiger, N. A., Siliņa, K., Cecconi, V., Lucchiari, G., Yagita∥, H., Guggisberg, E., Saba, S., Naščáková, Z., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.065 · Cited by 290 · see citing works
Vacchelli, E., Eggermont, A. M. M., Sautès‐Fridman, C., Galon, J., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2013) · OncoImmunology · doi:10.4161/onci.24612 · Cited by 255 · see citing works
Intralesional injection of herpes simplex virus 1716 in metastatic melanoma
MacKie, R. M., Stewart, B., & Brown, S. M. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04048-4 · Cited by 173 · see citing works
Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity
Ilkow, C. S., Marguerie, M., Batenchuk, C., Mayer, J., Ben Neriah, D., Cousineau, S., Falls, T., Jennings, V. A., Boileau, M., Bellamy, D., et al. (2015) · Nature Medicine · doi:10.1038/nm.3848 · Cited by 165 · see citing works
Yang, Z.-Z., Grote, D. M., Xiu, B., Ziesmer, S., Price-Troska, T. L., Hodge, L. S., Yates, D. M., Novak, A. J., & Ansell, S. M. (2014) · Leukemia · doi:10.1038/leu.2014.84 · Cited by 146 · see citing works
Hassona, Y. M., Cirillo, N., Heesom, K. J., Parkinson, E. K., & Prime, S. S. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.438 · Cited by 144 · see citing works
Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions
Park, D., Wershof, E., Boeing, S., Labernadie, A., Jenkins, R. P., George, S. L., Trepat, X., Bates, P. A., & Sahai, E. A. (2019) · Nature Materials · doi:10.1038/s41563-019-0504-3 · Cited by 129 · see citing works
Self-citationTrial Watch—Oncolytic viruses and cancer therapy
Pol, J. G., Buqué, A., Aranda, F., Bloy, N., Cremer, I., Eggermont, A. M. M., Erbs, P., Fucikova, J. P., Galon, J., Limacher, J., et al. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1117740 · Cited by 111 · see citing works
Wongthida, P., Díaz, R. M., Galivo, F., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4658 · Cited by 97 · see citing works
Activities of stromal and immune cells in HPV-related cancers
Júnior, M. R. B., de Melo, C. M. L., Barros, M. L. C. M. G., de Lima, R. D. C. P., de Freitas, A. C., & Venuti, A. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0802-7 · Cited by 79 · see citing works
Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents
Gaston, J., Cheradame, L., Yvonnet, V., Déas, O., Poupon, M., Judde, J., Cairo, S., & Goffin, V. (2016) · Oncotarget · doi:10.18632/oncotarget.12858 · Cited by 75 · see citing works
Armstrong, S. M., Khajoee, V., Wang, C., Wang, T., Tigdi, J., Yin, J., Kuebler, W. M., Gillrie, M. R., Davis, S. P., Ho, M., et al. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.12.002 · Cited by 67 · see citing works
Moloney, E. D., Kiely, J., & McNicholas, W. T. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04049-6 · Cited by 62 · see citing works
Role of Herpes Simplex Virus 1 γ34.5 in the Regulation of IRF3 Signaling
Manivanh, R. V., Mehrbach, J., Knipe, D. M., & Leib, D. A. (2017) · Journal of Virology · doi:10.1128/jvi.01156-17 · Cited by 55 · see citing works
Lee, W. L., Armstrong, S. M., Khajoee, V., Wang, C., Wang, T., Tigdi, J., Yin, J., Kuebler, W. M., Gillrie, M. R., Davis, S. P., et al. (2012) · The FASEB Journal · doi:10.1096/fasebj.26.1_supplement.862.1 · Cited by 16 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- [1]Gaggioli C Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells Nat Cell Biol 2007 9 1392 1400 18037882
- [2]Calvo F Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts Nat Cell Biol 2013 15 637 646 23708000 PMC3836234
- [3]Du P Kibbe WA Lin SM lumi: A pipeline for processing Illumina microarray Bioinformatics 2008 24 1547 1548 18467348
- [4]Smyth G Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments Statistical Applications in Genetics and Molecular Biology 2004 3 1 16646809
- [5]Puram SV Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer Cell 2017 171 1611 1624 e24 29198524 PMC5878932
- [6]Subramanian A Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles Proc Natl Acad Sci 2005 102 15545 15550 16199517 PMC1239896
- [7]Twyman-Saint Victor C Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer Nature 2015 10.1038/nature14292 PMC4401634 25754329 · DOI · Paper page
Cited by
Sorted by citations
Determinants and functions of CAFs secretome during cancer progression and therapy
Linares, J., Marín-Jiménez, J. A., Badia-Ramentol, J., & Calon, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.621070 · Cited by 110 · see citing works
cGAS-STING signaling encourages immune cell overcoming of fibroblast barricades in pancreatic cancer
Kabashima, A., Matsuo, Y., Ito, S., Akiyama, Y., Ishii, T., Shimada, S., Masamune, A., Tanabe, M., & Tanaka, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-14297-5 · Cited by 55 · see citing works
Current and emerging concepts for systemic treatment of metastatic colorectal cancer
Steup, C., Kennel, K. B., Neurath, M. F., Fichtner-Feigl, S., & Greten, F. R. (2025) · Gut · doi:10.1136/gutjnl-2025-335412 · Cited by 39 · see citing works
- Authors
- Arwert, E. N., Milford, E. L., Rullan, A., Derzsi, S., Hooper, S., Kato, T., Mansfield, D., Melcher, A., Harrington, K. J., & Sahai, E.
- Affiliations
- Institute of Cancer Research (GB)
- The Francis Crick Institute (GB)
- Corresponding author
- Sahai, Erik
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-06-01
- Volume
- 22
- Issue
- 7
- Pages
- 758-766
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC7611090
- OpenAlex
- W3031103936
- Cited by
- 90
- References
- 49
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 16 · 2023: 18 · 2022: 17 · 2021: 10 · 2020: 5
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-06-18)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (FC001144, A23275)
- RCUK | Medical Research Council (FC001144)
- Wellcome Trust (FC001144)
- Sociedad Española de Oncología Médica
- DH | National Institute for Health Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- cancer-associated fibroblasts, oncolytic viruses, STING, IRF3, interferon-beta, transcytosis, tumor stroma, interferon-stimulated genes, herpes simplex virus, tumor immunosuppression
- MeSH terms
- Cancer-Associated Fibroblasts, STING Protein, Adult, Animals, Carcinoma, Squamous Cell, Cells, Cultured, Humans, Male, Membrane Proteins, Mice, Inbred BALB C, Mice, Nude, Skin Neoplasms, Cytokines, Stromal Cells, Xenograft Model Antitumor Assays, Genomic Instability, Oncolytic Virotherapy, Oncolytic Viruses, Interferon Regulatory Factor-3, Mice, Host-Pathogen Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
