IFNAR1 stabilization sustains CD8 + T cell persistence in IFN-high colorectal cancer liver metastases
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-I high 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-I high tumors. These findings define a context-dependent IFN-I high / IFNAR1 low 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.
Authors
- Antonio Esposito (ORCID: https://orcid.org/0000-0002-1170-6266)
- Chiara Gnasso (ORCID: https://orcid.org/0000-0001-8005-5439)
- Gloria Delfanti (ORCID: https://orcid.org/0000-0002-3935-1057)
- Giulia Maria Scotti (ORCID: https://orcid.org/0000-0002-6929-4858)
- Barbara Clissi
- Andrea Monestiroli (ORCID: https://orcid.org/0000-0001-5818-2028)
- Charlotte Blanche Ekalle-Soppo (ORCID: https://orcid.org/0000-0001-7262-3539)
- Francesca Caruso (ORCID: https://orcid.org/0009-0003-7948-4924)
- Francesca Ratti (ORCID: https://orcid.org/0000-0002-8108-9064)
- Chiara Balestrieri (ORCID: https://orcid.org/0000-0001-7362-3530)
- Andrea Brendolan (ORCID: https://orcid.org/0000-0003-0109-6879)
- Claudio Doglioni (ORCID: https://orcid.org/0000-0002-4969-5216)
- Giovanni Tonon (ORCID: https://orcid.org/0000-0003-2973-5038)
- Paola Zordan (ORCID: https://orcid.org/0000-0001-6915-5535)
- Federica Cipriani (ORCID: https://orcid.org/0000-0002-8651-5982)
- Giulia Casorati (ORCID: https://orcid.org/0000-0002-5102-4112)
- Giovanni Sitia (ORCID: https://orcid.org/0000-0003-1024-9128)
- Vito Lampasona (ORCID: https://orcid.org/0000-0001-5162-8445)
- Luca G. Guidotti (ORCID: https://orcid.org/0000-0002-0205-2678)
- Riccardo Rosati (ORCID: https://orcid.org/0000-0002-2608-5749)
- Ugo Elmore (ORCID: https://orcid.org/0000-0001-9652-1502)
- Daniele V. F. Tauriello (ORCID: https://orcid.org/0000-0003-1522-3496)
- Valentina Buttiglione (ORCID: https://orcid.org/0000-0002-6815-4685)
- Oronza Antonietta Botrugno (ORCID: https://orcid.org/0000-0002-2568-9815)
- Ilaria Marzinotto (ORCID: https://orcid.org/0000-0002-4765-4509)
- Chiara Bonini (ORCID: https://orcid.org/0000-0002-0772-1674)
- Paolo Dellabona (ORCID: https://orcid.org/0000-0002-1414-633X)
- Eduard Batlle (ORCID: https://orcid.org/0000-0003-2422-0326)
- Lorena Maria Ferreira (ORCID: https://orcid.org/0000-0002-4262-0406)
- Federica Pedica (ORCID: https://orcid.org/0000-0003-0168-4718)
- Cristina Giordano (ORCID: https://orcid.org/0009-0008-4864-0388)
- Lucrezia Pierfederici (ORCID: https://orcid.org/0009-0005-3314-593X)
- Leonardo Andreoni (ORCID: https://orcid.org/0009-0005-2367-730X)
- Andrea Castiglioni (ORCID: https://orcid.org/0000-0002-4781-7355)
- Gabriele Metalli
- Iris Stefanetta (ORCID: https://orcid.org/0009-0007-0923-6465)
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Vita-Salute San Raffaele University (IT)
- Institute for Research in Biomedicine (ES)
- Barcelona Institute of Science and Technology (ES)
- IRCCS Ospedale San Raffaele (IT)
- Erasmus MC Cancer Institute (NL)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2026-11-04
- DOI
- https://doi.org/10.1126/sciadv.aei0181
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00