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

@article{castiglioni2026ifnar1,
  title = {{IFNAR1 stabilization sustains CD8+ T cell persistence in IFN-high colorectal cancer liver metastases}},
  author = {Andrea Castiglioni and Andrea Monestiroli and Gloria Delfanti and Paola Zordan and Cristina Giordano and Leonardo Andreoni and Barbara Clissi and Charlotte B. Ekalle-Soppo and Lorena M. Ferreira and Francesca Caruso and Valentina Buttiglione and Iris Stefanetta and Federica Pedica and Claudio Doglioni and Federica Cipriani and Francesca Ratti and Ugo Elmore and Riccardo Rosati and Chiara Gnasso and Antonio Esposito and Vito Lampasona and Ilaria Marzinotto and Oronza A. Botrugno and Gabriele Metalli and Giovanni Tonon and Giulia M. Scotti and Lucrezia Pierfederici and Chiara Balestrieri and Chiara Bonini and Daniele V.F. Tauriello and Eduard Batlle and Andrea Brendolan and Giulia Casorati and Paolo Dellabona and Luca G. Guidotti and Giovanni Sitia},
  journal = {Science Advances},
  year = {2026},
  month = nov,
  doi = {10.1126/sciadv.aei0181},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aei0181},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - IFNAR1 stabilization sustains CD8+ T cell persistence in IFN-high colorectal cancer liver metastases
AU  - Andrea Castiglioni
AU  - Andrea Monestiroli
AU  - Gloria Delfanti
AU  - Paola Zordan
AU  - Cristina Giordano
AU  - Leonardo Andreoni
AU  - Barbara Clissi
AU  - Charlotte B. Ekalle-Soppo
AU  - Lorena M. Ferreira
AU  - Francesca Caruso
AU  - Valentina Buttiglione
AU  - Iris Stefanetta
AU  - Federica Pedica
AU  - Claudio Doglioni
AU  - Federica Cipriani
AU  - Francesca Ratti
AU  - Ugo Elmore
AU  - Riccardo Rosati
AU  - Chiara Gnasso
AU  - Antonio Esposito
AU  - Vito Lampasona
AU  - Ilaria Marzinotto
AU  - Oronza A. Botrugno
AU  - Gabriele Metalli
AU  - Giovanni Tonon
AU  - Giulia M. Scotti
AU  - Lucrezia Pierfederici
AU  - Chiara Balestrieri
AU  - Chiara Bonini
AU  - Daniele V.F. Tauriello
AU  - Eduard Batlle
AU  - Andrea Brendolan
AU  - Giulia Casorati
AU  - Paolo Dellabona
AU  - Luca G. Guidotti
AU  - Giovanni Sitia
PY  - 2026
DA  - 2026/11/04
JO  - Science Advances
DO  - 10.1126/sciadv.aei0181
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aei0181
AB  - 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.
SN  - 2375-2548
ER  -