Synergistic checkpoint-blockade and radiotherapy-radiodynamic therapy via an immunomodulatory nanoscale metal-organic framework.
Nat Biomed Eng
; 6(2): 144-156, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-35190678
ABSTRACT
Checkpoint blockade elicits durable responses in immunogenic cancers, but it is largely ineffective in immunologically 'cold' tumours. Here we report the design, synthesis and performance of a bismuth-based nanoscale metal-organic framework that modulates the immunological and mechanical properties of the tumour microenvironment for enhanced radiotherapy-radiodynamic therapy. In mice with non-immunogenic prostate and pancreatic tumours irradiated with low X-ray doses, the intratumoural injection of the radiosensitizer mediated potent outcomes via the repolarization of immunosuppressive M2 macrophages into immunostimulatory M1 macrophages, the reduction of the concentration of intratumoural transforming growth factor beta (TGF-ß) and of collagen density, and the inactivation of cancer-associated fibroblasts. When intravenously injected in combination with checkpoint-blockade therapy, the radiosensitizer mediated the reversal of immunosuppression in primary and distant tumours via the systemic reduction of TGF-ß levels, which led to the downregulation of collagen expression, the stimulation of T-cell infiltration in the tumours and a robust abscopal effect. Nanoscale radiosensitizers that stimulate anti-tumour immunity and T-cell infiltration may enhance the therapeutic outcomes of checkpoint blockade in other tumour types.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Estructuras Metalorgánicas
/
Neoplasias
Límite:
Animals
Idioma:
En
Revista:
Nat Biomed Eng
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos