Radiotherapy synergizes with an inducible AAV-based immunotherapy platform to program local and systemic antitumor immunity

  • Cancer Cell. 2026 May 11;44(5):995-1011.e12. doi: 10.1016/j.ccell.2026.02.013.
Sonia Marco  1 ,  Myriam Fernández  1 ,  Beatriz Honorato  1 ,  Nerea Juanarena  1 ,  Cristina Sainz  1 ,  Ainhoa Andueza  1 ,  David J Gould  2 ,  Seth Anderson  3 ,  Carlos de Andrea  4 ,  Paulo Pérez Domínguez  4 ,  Paolo Wong  1 ,  Carlos Vásquez  1 ,  Irene Narinda  1 ,  Carmen Unzu  5 ,  Sergio Isola  5 ,  Beatriz Tavira  1 ,  Mikel Ariz  6 ,  Gracián Camps  7 ,  Miguel F Sanmamed  8 ,  Julián Pardo  9 ,  Sara Labiano  10 ,  Marta M Alonso  10 ,  Javier Marco-Sanz  10 ,  Elizabeth Guruceaga  11 ,  María Collantes  12 ,  Jon Ander Simón  13 ,  Iván Peñuelas  13 ,  Joaquín Fernández-Irigoyen  14 ,  Enrique Santamaría  14 ,  Jesús Prieto  15 ,  Juan Dubrot  16
Affiliations
  • 1. Solid Tumors Program, Cima-Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain.
  • 2. Centre for Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.
  • 3. Broad Institute, Cambridge, MA, USA.
  • 4. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Department of Pathology, CUN-Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain.
  • 5. Gene Therapy for Rare Diseases Program, Cima-Universidad de Navarra, Pamplona, Spain.
  • 6. Department of Electrical, Electronic and Communications Engineering, Public University of Navarra, Pamplona, Spain.
  • 7. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Immunotherapy and Immunology Program, Cima-Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain.
  • 8. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Immunotherapy and Immunology Program, Cima-Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Department of Medical Oncology, CUN, Cima-Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain.
  • 9. CIBER Enfermedades Infecciosas. Instituto de Salud Carlos III. Dpto. Microbiologia Radiología Pediatría y Salud Pública. Fac Medicina. Universidad de Zaragoza/IIS Aragon, Zaragoza, Spain.
  • 10. Solid Tumors Program, Cima-Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Department of Pediatrics, CUN, Pamplona, Spain.
  • 11. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Bioinformatics Platform, Cima-Universidad de Navarra, Pamplona, Spain.
  • 12. Broad Institute, Cambridge, MA, USA; Translational Molecular Imaging and Radiopharmacy Unit, CUN, Pamplona, Spain.
  • 13. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Translational Molecular Imaging and Radiopharmacy Unit, CUN, Pamplona, Spain.
  • 14. Proteomics Platform, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.
  • 15. Solid Tumors Program, Cima-Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain. Electronic address: [email protected].
  • 16. Solid Tumors Program, Cima-Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain. Electronic address: [email protected].
PMID: 41875889 DOI: 10.1016/j.ccell.2026.02.013
Abstract

Radiotherapy (RT) can prime the immune system against Cancer but often fails to generate effective antitumor responses due to concomitant induction of immunosuppressive factors. To overcome this limitation, we built upon the observation that RT enhances adeno-associated vectors (AAVs) tumor transduction through the epigenetic modification of vector episomes. We designed an AAV-based platform to deliver immunostimulatory cytokines through an interferon (IFN)-inducible promoter that allows for spatial control of transgene expression into irradiated tumors. As opposed to a constitutive system, local delivery of a vector encoding for inducible IL-12 (AAV-iIL12) achieves an efficient production of the cytokine without significant toxicity. Combination of RT and AAV-iIL12 generates a highly immunostimulatory tumor microenvironment (TME) leading to robust local and systemic antitumor responses in an IFNγ- and FAS-dependent manner, able to overcome common immune-evasion mechanisms. Our work shows that radiation coupled with AAV-based immune-gene delivery is an efficient and safe approach to treat Cancer.

Keywords
AAV; IL-12; cancer gene therapy; epigenetic regulation; immunotherapy; radiotherapy; systemic immunity; tumor microenvironment.
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