2. Academic Validation
  3. Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer

Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer

  • Signal Transduct Target Ther. 2025 Jun 13;10(1):185. doi: 10.1038/s41392-025-02271-2.
Borja Ruiz-Fernández de Córdoba # 1,  Karmele Valencia # 1 2 3,  Connor Welch 1,  Haritz Moreno 1,  Susana Martínez-Canarias 1,  Carolina Zandueta 1,  Eduardo Gómez 1,  Alfonso Calvo 1 2 3 4,  Nerea Otegui 1,  Mirari Echepare 1 2 5,  Ignacio Garzón 1,  Daniel Ajona 1 2 3,  David Lara-Astiaso 6 7,  Elisabeth Guruceaga 2 8,  Laura Guembe 5 9,  Rubén Pío 1 2 3 10,  Ignacio Melero 2 3 11 12,  Silve Vicent 1 2 3 5,  Fernando Pastor 2 3 4 10,  Rafael Martínez-Monge 13 14 15 16 17,  Fernando Lecanda 18 19 20
Affiliations

Affiliations

  • 1 Solid Tumors Program. Division of Oncology, Center for Applied Medical Research (CIMA)-University of Navarra, Pamplona, Spain.
  • 2 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
  • 3 Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 4 Molecular Therapeutics and Innovation Therapeutics Programs, CIMA-University of Navarra, Pamplona, Spain.
  • 5 Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
  • 6 Department of Haemato-oncology, University of Cambridge, Cambridge, UK.
  • 7 Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute, Cambridge, UK.
  • 8 Bioinformatics Core Facility, CIMA-University of Navarra, Pamplona, Spain.
  • 9 Morphology Core Facility, CIMA-University of Navarra, Pamplona, Spain.
  • 10 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
  • 11 Immunology and Immunotherapy, CIMA-University of Navarra and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain.
  • 12 Oncology, Clínica, University of Navarra, CCUN, Pamplona, Spain.
  • 13 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. rmartinezm@unav.es.
  • 14 Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. rmartinezm@unav.es.
  • 15 Oncology, Clínica, University of Navarra, CCUN, Pamplona, Spain. rmartinezm@unav.es.
  • 16 Radiation Oncology, Clínica University of Navarra, CCUN, Pamplona, Spain. rmartinezm@unav.es.
  • 17 Surgery, Clínica University of Navarra, CCUN, Pamplona, Spain. rmartinezm@unav.es.
  • 18 Solid Tumors Program. Division of Oncology, Center for Applied Medical Research (CIMA)-University of Navarra, Pamplona, Spain. flecanda@unav.es.
  • 19 Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. flecanda@unav.es.
  • 20 Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain. flecanda@unav.es.
  • # Contributed equally.
PMID: 40506449 DOI: 10.1038/s41392-025-02271-2
Abstract

The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast Cancer (TNBC), primarily by contributing to tumor cell survival and treatment resistance. However, the precise mechanisms remain unclear. In a model of local recurrence (LR), circulating tumor cells (CTC) engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients, suggesting ENPP1´s role in genome integrity. Blockade of ENPP1 using a permeable ENPP1 inhibitor (AVA-NP-695) reduced radioresistance, mechanistically attributed to decreased homologous recombination (HR) resulting in persistent DNA damage, as evidenced by enhanced tail moment and sustained γH2AX formation. This impaired DNA damage repair (DDR) sensitized tumor cells to ionizing radiation (IR). Notably, several DDR inhibitors (i) (including PARPi and ATMi) showed the highest synergy score in a targeted pharmacological screening. In vivo, dual ENPP1/ATM inhibition heightened radiosensitivity, compromised tumor cell survival and enhanced STING-TBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis. This resulted in robust innate and long-lasting adaptive antitumor immune memory responses, leading to significant tumor regression. Remarkably, combined treatment post-IR reduced spontaneous metastasis and local recurrence, and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models. Thus, these findings position ENPP1 as a critical link between genome integrity and immunosuppression, offering promising translational opportunities for treating local or distant dissemination in TNBC.

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