TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages

  • Nat Genet. 2025 Dec;57(12):3050-3065. doi: 10.1038/s41588-025-02380-2.
Ana Henriques  #  1  2 ,  Maria Salvany-Celades  #  1  2 ,  Paula Nieto  3 ,  Sergio Palomo-Ponce  1  2 ,  Marta Sevillano  1  2 ,  Xavier Hernando-Momblona  1  2 ,  Emily Middendorp-Guerra  1  2 ,  Montserrat Llanses Martinez  1 ,  Elisabeth Marjolein Haak  1 ,  Juan Nieto  3 ,  Ginevra Caratú  3 ,  Domenica Marchese  3 ,  Max Ruiz Gil  3 ,  Sebastien Tosi  1  4 ,  Theresa Suckert  1 ,  Jordi Badia-Ramentol  1  5 ,  Adrià Caballé-Mestres  1 ,  Carolina Sanchez-Zarzalejo  1 ,  Lidia Mateo  1 ,  Daniele V F Tauriello  1  6 ,  Antoni Riera  1  7 ,  Elena Sancho  1  2 ,  Camille Stephan-Otto Attolini  1 ,  Alejandro Prados  8  9 ,  Holger Heyn  10  11  12 ,  Eduard Batlle  13  14  15
Affiliations
  • 1. Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 2. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
  • 3. Centro Nacional de Análisis Genómico, Barcelona, Spain.
  • 4. Biophysics in Cell Biology, Universitat Pompeu Fabra, Barcelona, Spain.
  • 5. Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain.
  • 6. Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.
  • 7. Universitat de Barcelona, Barcelona, Spain.
  • 8. Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology, Barcelona, Spain. [email protected].
  • 9. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. [email protected].
  • 10. Centro Nacional de Análisis Genómico, Barcelona, Spain. [email protected].
  • 11. Universitat de Barcelona, Barcelona, Spain. [email protected].
  • 12. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. [email protected].
  • 13. Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology, Barcelona, Spain. [email protected].
  • 14. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. [email protected].
  • 15. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. [email protected].
  • # Contributed equally.
PMID: 41203813 DOI: 10.1038/s41588-025-02380-2
Abstract

Transforming growth factor β (TGF-β) signaling in the tumor microenvironment predicts resistance to immune checkpoint blockade (ICB). While TGF-β inhibition enhances ICB efficacy in murine Cancer models, clinical trials have yet to demonstrate benefit, underscoring the need to better understand its immunoregulatory roles across disease contexts. Using mouse models of advanced colorectal Cancer and patient-derived data, we demonstrate that TGF-β impairs antitumor immunity at multiple levels in liver metastases. It acts directly on T cells to block recruitment of peripheral memory CD8+ T cells, thereby limiting the effectiveness of ICB. Concurrently, TGF-β instructs tumor-associated macrophages to suppress clonal expansion of newly arrived T cells by inducing SPP1 expression. This extracellular matrix protein promotes Collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, ultimately driving ICB resistance. Our findings reveal how TGF-β coordinates immunosuppressive mechanisms across innate and adaptive immune compartments to promote metastasis, offering new avenues to improve immunotherapy in colorectal Cancer.

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