{ "abstract": "Colorectal cancer liver metastases (CRC-LMs) are associated with poor survival and frequently resist immunotherapy, yet the mechanisms underlying this immune refractoriness remain incompletely defined. Here, we identify a tumor-intrinsic type I interferon (IFN-I)–high state in CRC-LMs associated with loss of the IFN-α/β receptor subunit 1 (IFNAR1) on effector T lymphocytes within immune-enriched perimetastatic niches. Reduced IFNAR1 expression stratifies patients with poor clinical outcomes. Transcriptional profiling of patient-derived organoids and complementary preclinical models revealed heterogeneous but recurrent tumor-derived IFN-I production in CRC-LMs. In IFN-Ihigh contexts, sustained signaling promoted IFNAR1 internalization on effector CD8+ T cells, impairing their persistence, survival, and effector function. Pharmacologic or genetic stabilization of IFNAR1 on cell surface restored CD8+ T cell fitness and selectively enhanced T cell receptor– and chimeric antigen receptor–based immunotherapies in IFN-Ihigh tumors. These findings define a context-dependent IFN-Ihigh / IFNAR1low axis that constrains antitumor immunity in CRC-LMs and identify IFNAR1 stabilization as a strategy to convert chronic IFN signaling from a suppressive barrier into a therapeutic vulnerability.", "abstract_shown": true, "affiliations": [ "Institute of Immunology and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.", "Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.", "Vita-Salute San Raffaele University, Milan, Italy.", "Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, Milan, Italy.", "Department of Gastrointestinal Surgery, IRCCS San Raffaele Hospital, Milan, Italy.", "Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.", "Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.", "Comprehensive Cancer Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.", "Center for Omics Sciences, IRCCS San Raffaele Hospital, Milan, Italy.", "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.", "Departments of Medical Oncology and of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands.", "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.", "Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain." ], "article_type": "Research Article", "arxiv": null, "author_total": 36, "authors": [ { "affs": [ 0 ], "name": "Andrea Castiglioni", "orcid": "0000-0002-4781-7355" }, { "affs": [ 0 ], "name": "Andrea Monestiroli", "orcid": "0000-0001-5818-2028" }, { "affs": [ 0 ], "name": "Gloria Delfanti", "orcid": "0000-0002-3935-1057" }, { "affs": [ 0 ], "name": "Paola Zordan" }, { "affs": [ 0 ], "name": "Cristina Giordano", "orcid": "0009-0008-4864-0388" }, { "affs": [ 0 ], "name": "Leonardo Andreoni", "orcid": "0009-0005-2367-730X" }, { "affs": [ 0 ], "name": "Barbara Clissi", "orcid": "0000-0001-5299-6012" }, { "affs": [ 0 ], "name": "Charlotte B. Ekalle-Soppo" }, { "affs": [ 0 ], "name": "Lorena M. Ferreira", "orcid": "0000-0002-4262-0406" }, { "affs": [ 0 ], "name": "Francesca Caruso" }, { "affs": [ 0 ], "name": "Valentina Buttiglione" }, { "affs": [ 0 ], "name": "Iris Stefanetta", "orcid": "0009-0007-0923-6465" }, { "affs": [ 1, 2 ], "name": "Federica Pedica", "orcid": "0000-0003-0168-4718" }, { "affs": [ 1, 2 ], "name": "Claudio Doglioni", "orcid": "0000-0002-4969-5216" }, { "affs": [ 2, 3 ], "name": "Federica Cipriani", "orcid": "0000-0002-8651-5982" }, { "affs": [ 2, 3 ], "name": "Francesca Ratti", "orcid": "0000-0002-8108-9064" }, { "affs": [ 2, 4 ], "name": "Ugo Elmore" }, { "affs": [ 2, 4 ], "name": "Riccardo Rosati", "orcid": "0000-0002-2608-5749" }, { "affs": [ 2, 5 ], "name": "Chiara Gnasso" }, { "affs": [ 2, 5 ], "name": "Antonio Esposito", "orcid": "0000-0002-1170-6266" }, { "affs": [ 6 ], "name": "Vito Lampasona", "orcid": "0000-0001-5162-8445" }, { "affs": [ 6 ], "name": "Ilaria Marzinotto", "orcid": "0000-0002-4765-4509" }, { "affs": [ 2, 7 ], "name": "Oronza A. Botrugno", "orcid": "0000-0002-2568-9815" }, { "affs": [ 7 ], "name": "Gabriele Metalli" }, { "affs": [ 2, 7, 8 ], "name": "Giovanni Tonon", "orcid": "0000-0003-2973-5038" }, { "affs": [ 8 ], "name": "Giulia M. Scotti", "orcid": "0000-0002-6929-4858" }, { "affs": [ 0, 8 ], "name": "Lucrezia Pierfederici", "orcid": "0009-0005-3314-593X" }, { "affs": [ 0, 8 ], "name": "Chiara Balestrieri", "orcid": "0000-0001-7362-3530" }, { "affs": [ 0, 2 ], "name": "Chiara Bonini", "orcid": "0000-0002-0772-1674" }, { "affs": [ 9, 10 ], "name": "Daniele V.F. Tauriello", "orcid": "0000-0003-1522-3496" }, { "affs": [ 9, 11, 12 ], "name": "Eduard Batlle", "orcid": "0000-0003-2422-0326" }, { "affs": [ 7 ], "name": "Andrea Brendolan", "orcid": "0000-0003-0109-6879" }, { "affs": [ 0 ], "name": "Giulia Casorati", "orcid": "0000-0002-5102-4112" }, { "affs": [ 0 ], "name": "Paolo Dellabona", "orcid": "0000-0002-1414-633X" }, { "affs": [ 0, 2 ], "name": "Luca G. Guidotti", "orcid": "0000-0002-0205-2678" }, { "affs": [ 0 ], "name": "Giovanni Sitia", "orcid": "0000-0003-1024-9128" } ], "bibtex": "https://research.draconitic.com/paper/6dj21yj2e7dbv.bib", "cited_by": 0, "doi": "10.1126/sciadv.aei0181", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13733802/", "id": "6dj21yj2e7dbv", "issns": [ "2375-2548" ], "landing_url": "https://www.science.org/doi/abs/10.1126/sciadv.aei0181", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Biomedicine and Life Sciences" ], [ "heading", "Cancer" ], [ "heading", "Immunology" ], [ "heading", "Research Article" ], [ "heading", "SciAdv r-articles" ] ], "openalex": null, "pdf_url": null, "pmcid": "PMC13733802", "pmid": "42981393", "published": "2026-11-04", "publisher": "American Association for the Advancement of Science (AAAS)", "ris": "https://research.draconitic.com/paper/6dj21yj2e7dbv.ris", "sources": [ { "first_seen": "2026-11-05T00:20:34Z", "native_id": "10.1126/sciadv.aei0181", "source": "feed-science", "url": "https://www.science.org/doi/abs/10.1126/sciadv.aei0181" }, { "first_seen": "2026-11-05T00:20:35Z", "native_id": "10.1126/sciadv.aei0181", "source": "crossref", "url": "https://www.science.org/doi/10.1126/sciadv.aei0181" }, { "first_seen": "2026-11-08T12:23:30Z", "native_id": "PMC13733802", "source": "pmc", "url": "https://doi.org/10.1126/sciadv.aei0181" } ], "subjects": [ { "field": "biology", "origin": "heading:Immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "heading:Cancer", "subfield": "oncology" } ], "title": "IFNAR1 stabilization sustains CD8+ T cell persistence in IFN-high colorectal cancer liver metastases", "title_text": "IFNAR1 stabilization sustains CD8+ T cell persistence in IFN-high colorectal cancer liver metastases", "type": "peer-reviewed", "updated_at": "2026-11-08T12:23:30Z", "url": "https://research.draconitic.com/paper/6dj21yj2e7dbv", "venue": "Science Advances", "versions": [] }