Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-γ response pathway activation.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:39424359", "kind": "science-record", "revision": 3, "content_hash": "sha256:f4b3624badd34439c518deb24377eafb92793595437f95d44cc6d9c9604eaa92", "created_at": "2026-11-01T20:29:40Z", "updated_at": "2026-11-01T22:55:26Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Interferon-induced factor 16 is essential in metastatic melanoma to maintain STING levels and the immune responses upon IFN-γ response pathway activation.", "doi": "10.1136/jitc-2024-009590", "pmid": "39424359", "authors": ["Yuta Kobayashi", "Matias A Bustos", "Yoshinori Hayashi", "Qiang Yu", "Dave Hoon"], "journal": "Journal for immunotherapy of cancer", "year": 2024, "abstract": "BACKGROUND: 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)-γ-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-γ stimulation and the connection to ICIs response remains not completely understood.\nMETHODS: 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.\nRESULTS: Deconvolution analysis showed that high-IFI16 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-κB) signaling pathways, independent of cyclic GMP-AMP synthase or absent in melanoma 2, on IFN-γ stimulation. IFI16 knockdown significantly decreased CXCL10 and ICAM1 secretion. EZH2 inhibitor reversed the repressive epigenetic control on IFI16 to promote STING and NF-κB signaling pathways on IFN-γ 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.\nCONCLUSIONS: This study identifies IFI16 as a key sensor during IFN-γ 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.", "claims": [{"id": "claim-method", "statement": "Overall survival was analyzed using the Kaplan-Meier method and log-rank test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39424359", "locator": "sections[12] \"Biostatistics analysis\" paragraph 2", "quote": "Overall survival was analyzed using the Kaplan-Meier method and log-rank test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data are available in a public, open access repository.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39424359", "locator": "sections[28] \"Data availability statement\" paragraph 2", "quote": "Data are available in a public, open access repository."}], "state": "complete"}, {"id": "claim-target-result", "statement": "High-IFI16 mRNA levels were significantly associated with good prognosis in patients with AJCC stage III and IV melanoma.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:39424359", "locator": "sections[15] \"IFI16 mRNA levels and prognosis of metastatic melanomas\" paragraph 4", "quote": "High-IFI16 mRNA levels were significantly associated with good prognosis in patients with AJCC stage III and IV melanoma (figure 1G–I)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "High-IFI16 mRNA levels were significantly associated with good prognosis in patients with AJCC stage III and IV melanoma.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:39424359"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE154996"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE154996"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:39424359", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1136/jitc-2024-009590", "sha256": 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