{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:57:42Z","timestamp":1790740662519,"version":"4.1.0"},"reference-count":50,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"unspecified","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"publisher","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}],"id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,9,30]]},"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Immune checkpoint inhibitor (ICIs)-based therapies are the standard of care treatment for patients with metastatic melanoma (MM). The stimulator of interferon genes (STING) signaling pathway is critical in controlling immune responses to ICIs. Interferon (IFN)-\u03b3-inducible protein 16 (IFI16) is a cytosolic DNA sensor that activates the STING signaling pathway. The link between IFI16 and STING signaling pathway on IFN-\u03b3 stimulation and the connection to ICIs response remains not completely understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Deconvolution analyses were performed using the TCGA-SKCM, GSE91061, and PRJEB23709 public RNA sequencing (RNA-seq) data sets that contained RNA-seq for patients with MM. Functional assays combined with cytokine arrays were performed using MM cell lines to validate in silico data. Multiplex immunofluorescence was performed on untreated or pretreatment tumor samples from patients with MM.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Deconvolution analysis showed that high-<jats:italic>IFI16<\/jats:italic> levels in melanoma cells were associated with a good prognosis in patients with MM and positively correlated with M1-macrophage infiltration. Functional assays using MM cell lines demonstrated that IFI16 is a key molecule to sense cytosolic DNA and activate STING and nuclear factor kappa B (NF-\u03baB) signaling pathways, independent of cyclic GMP-AMP synthase or absent in melanoma 2, on IFN-\u03b3 stimulation. IFI16 knockdown significantly decreased CXCL10 and ICAM1 secretion. EZH2 inhibitor reversed the repressive epigenetic control on IFI16 to promote STING and NF-\u03baB signaling pathways on IFN-\u03b3 stimulation. Increased IFI16, ICAM1, and CXCL10 levels in tumor samples from patients with MM were positively correlated with M1-macrophage infiltration and a significantly better response to ICIs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study identifies IFI16 as a key sensor during IFN-\u03b3 stimulation associated with ICI response, and it proposes the epigenetic EZH2 inhibitor as an alternative treatment strategy to overcome ICI resistance in patients with MM.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-009590","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T14:00:19Z","timestamp":1729260019000},"page":"e009590","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-\u03b3 response pathway activation"],"prefix":"10.1136","volume":"12","author":[{"given":"Yuta","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Dept. of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9625-1127","authenticated-orcid":false,"given":"Matias A","family":"Bustos","sequence":"additional","affiliation":[{"name":"Dept. of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Dept. of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science Technology and Research, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave","family":"Hoon","sequence":"additional","affiliation":[{"name":"Dept. of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"2025100302344605000_12.10.e009590.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2034861"},{"key":"2025100302344605000_12.10.e009590.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2109970"},{"key":"2025100302344605000_12.10.e009590.3","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature New Biol"},{"key":"2025100302344605000_12.10.e009590.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1604958"},{"key":"2025100302344605000_12.10.e009590.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.017"},{"key":"2025100302344605000_12.10.e009590.6","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s13578-023-01151-y","article-title":"MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer","volume":"13","author":"Bustos","year":"2023","journal-title":"Cell Biosci"},{"key":"2025100302344605000_12.10.e009590.7","doi-asserted-by":"crossref","DOI":"10.1002\/ctm2.985","article-title":"UBQLN4 promotes STING proteasomal degradation during cisplatin-induced DNA damage in triple-negative breast cancer","volume":"12","author":"Shoji","year":"2022","journal-title":"Clin Transl Med"},{"key":"2025100302344605000_12.10.e009590.8","doi-asserted-by":"publisher","DOI":"10.1038\/nri3452"},{"key":"2025100302344605000_12.10.e009590.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.03.056"},{"key":"2025100302344605000_12.10.e009590.10","doi-asserted-by":"crossref","unstructured":"Pandey V , Fleming-Martinez A , Bastea L , et al . CXCL10\/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions. Elife 2021;10. doi:10.7554\/eLife.60646","DOI":"10.7554\/eLife.60646"},{"key":"2025100302344605000_12.10.e009590.11","doi-asserted-by":"crossref","first-page":"1176647","DOI":"10.3389\/fimmu.2023.1176647","article-title":"Role of ICAM1 in tumor immunity and prognosis of triple-negative breast cancer","volume":"14","author":"Zhou","year":"2023","journal-title":"Front Immunol"},{"key":"2025100302344605000_12.10.e009590.12","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms14391","article-title":"IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP","volume":"8","author":"J\u00f8nsson","year":"2017","journal-title":"Nat Commun"},{"key":"2025100302344605000_12.10.e009590.13","doi-asserted-by":"crossref","unstructured":"Falahat R , Berglund A , Putney RM , et al . Epigenetic reprogramming of tumor cell\u2013intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. Proc Natl Acad Sci USA 2021;118. doi:10.1073\/pnas.2013598118","DOI":"10.1073\/pnas.2013598118"},{"key":"2025100302344605000_12.10.e009590.14","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/s41564-021-00907-x","article-title":"IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection","volume":"6","author":"Jiang","year":"2021","journal-title":"Nat Microbiol"},{"key":"2025100302344605000_12.10.e009590.15","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2201376119","article-title":"IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer","volume":"119","author":"Ong","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025100302344605000_12.10.e009590.16","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s43018-022-00356-3","article-title":"Cell type and gene expression deconvolution with BayesPrism enables Bayesian integrative analysis across bulk and single-cell RNA sequencing in oncology","volume":"3","author":"Chu","year":"2022","journal-title":"Nat Cancer"},{"key":"2025100302344605000_12.10.e009590.17","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-21-0887"},{"key":"2025100302344605000_12.10.e009590.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0546-8"},{"key":"2025100302344605000_12.10.e009590.19","doi-asserted-by":"publisher","DOI":"10.1016\/J.CCELL.2019.01.003"},{"key":"2025100302344605000_12.10.e009590.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.028"},{"key":"2025100302344605000_12.10.e009590.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.08.005"},{"key":"2025100302344605000_12.10.e009590.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0114-2"},{"key":"2025100302344605000_12.10.e009590.23","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-019-0638-6","article-title":"Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data","volume":"11","author":"Finotello","year":"2019","journal-title":"Genome Med"},{"key":"2025100302344605000_12.10.e009590.24","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-0327-7_17"},{"key":"2025100302344605000_12.10.e009590.25","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol"},{"key":"2025100302344605000_12.10.e009590.26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407"},{"key":"2025100302344605000_12.10.e009590.27","doi-asserted-by":"crossref","DOI":"10.1038\/s41698-023-00474-w","article-title":"Spatial profiling of cancer-associated fibroblasts of sporadic early onset colon cancer microenvironment","volume":"7","author":"Furuhashi","year":"2023","journal-title":"NPJ Precis Oncol"},{"key":"2025100302344605000_12.10.e009590.28","doi-asserted-by":"crossref","DOI":"10.1186\/1755-8794-2-18","article-title":"PrognoScan: a new database for meta-analysis of the prognostic value of genes","volume":"2","author":"Mizuno","year":"2009","journal-title":"BMC Med Genomics"},{"key":"2025100302344605000_12.10.e009590.29","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2022.2044103","article-title":"IFN-\u03b3 activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation","volume":"11","author":"Xiong","year":"2022","journal-title":"Oncoimmunology"},{"key":"2025100302344605000_12.10.e009590.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.006"},{"key":"2025100302344605000_12.10.e009590.31","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms9971","article-title":"Systematic pan-cancer analysis of tumour purity","volume":"6","author":"Aran","year":"2015","journal-title":"Nat Commun"},{"key":"2025100302344605000_12.10.e009590.32","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: from bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Sig Transduct Target Ther"},{"key":"2025100302344605000_12.10.e009590.33","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0146"},{"key":"2025100302344605000_12.10.e009590.34","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-21707-1","article-title":"Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains","volume":"12","author":"Gopi","year":"2021","journal-title":"Nat Commun"},{"key":"2025100302344605000_12.10.e009590.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109410"},{"key":"2025100302344605000_12.10.e009590.36","doi-asserted-by":"publisher","DOI":"10.3390\/v12121464"},{"key":"2025100302344605000_12.10.e009590.37","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2148-12-140","article-title":"The mammalian PYHIN gene family: phylogeny, evolution and expression","volume":"12","author":"Cridland","year":"2012","journal-title":"BMC Evol Biol"},{"key":"2025100302344605000_12.10.e009590.38","doi-asserted-by":"crossref","first-page":"912133","DOI":"10.3389\/fbioe.2022.912133","article-title":"The Dynamic Feature of Macrophage M1\/M2 Imbalance Facilitates the Progression of Non-Traumatic Osteonecrosis of the Femoral Head","volume":"10","author":"Tan","year":"2022","journal-title":"Front Bioeng Biotechnol"},{"key":"2025100302344605000_12.10.e009590.39","doi-asserted-by":"crossref","DOI":"10.1093\/annonc\/mdy424.015","article-title":"Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas","volume":"29","author":"Harrington","year":"2018","journal-title":"Ann Oncol"},{"key":"2025100302344605000_12.10.e009590.40","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-023-01725-x","article-title":"Roles of tumor-associated macrophages in anti-PD-1\/PD-L1 immunotherapy for solid cancers","volume":"22","author":"Zhang","year":"2023","journal-title":"Mol Cancer"},{"key":"2025100302344605000_12.10.e009590.41","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2015.209"},{"key":"2025100302344605000_12.10.e009590.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022"},{"key":"2025100302344605000_12.10.e009590.43","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s43018-020-0036-4","article-title":"Long-distance modulation of bystander tumor cells by CD8+ T-cell-secreted IFN-\u03b3","volume":"1","author":"Hoekstra","year":"2020","journal-title":"Nat Cancer"},{"key":"2025100302344605000_12.10.e009590.44","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-022-03844-3","article-title":"SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma","volume":"20","author":"Li","year":"2022","journal-title":"J Transl Med"},{"key":"2025100302344605000_12.10.e009590.45","doi-asserted-by":"publisher","DOI":"10.1007\/S00262-017-1975-1\/FIGURES\/5"},{"key":"2025100302344605000_12.10.e009590.46","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.2MR0220-549R"},{"key":"2025100302344605000_12.10.e009590.47","doi-asserted-by":"crossref","unstructured":"Cacho-Navas C , L\u00f3pez-Pujante C , Reglero-Real N , et al . ICAM-1 nanoclusters regulate hepatic epithelial cell polarity by leukocyte adhesion-independent control of apical actomyosin. Elife 2024;12. doi:10.7554\/eLife.89261","DOI":"10.7554\/eLife.89261.3"},{"key":"2025100302344605000_12.10.e009590.48","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-4121"},{"key":"2025100302344605000_12.10.e009590.49","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2020-5449"},{"key":"2025100302344605000_12.10.e009590.50","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.jid.2021.08.437","article-title":"EZH2 Inhibitor Enhances the STING Agonist\u2012Induced Antitumor Immunity in Melanoma","volume":"142","author":"Xu","year":"2022","journal-title":"J Invest Dermatol"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2024-009590","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T09:34:59Z","timestamp":1759484099000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2024-009590"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,18]]},"published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1136\/jitc-2024-009590"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2024-009590","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10]]}}}