IFNAR1 stabilization sustains CD8⁺ T cell persistence in IFN-high colorectal cancer liver metastases.

Authors

Andrea Castiglioni, Andrea Monestiroli, Gloria Delfanti, Paola Zordan, Cristina Giordano, Leonardo Andreoni, Barbara Clissi, Charlotte B Ekalle-Soppo, Lorena M Ferreira, Francesca Caruso, Valentina Buttiglione, Iris Stefanetta, Federica Pedica, Claudio Doglioni, Federica Cipriani, Francesca Ratti, Ugo Elmore, Riccardo Rosati, Chiara Gnasso, Antonio Esposito, Vito Lampasona, Ilaria Marzinotto, Oronza A Botrugno, Gabriele Metalli, Giovanni Tonon, Giulia M Scotti, Lucrezia Pierfederici, Chiara Balestrieri, Chiara Bonini, Daniele V F Tauriello, Eduard Batlle, Andrea Brendolan, Giulia Casorati, Paolo Dellabona, Luca G Guidotti, Giovanni Sitia

Published in

Science advances. Volume 12. Issue 45. Pages eaei0181. Nov 06, 2026. Epub Nov 04, 2026.

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-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.

PMID:
42981393
Bibliographic data and abstract were imported from PubMed on 05 Nov 2026.

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