放射增敏剂
封锁
癌症研究
放射治疗
背向效应
免疫检查点
医学
肿瘤微环境
免疫疗法
免疫系统
免疫学
受体
内科学
肿瘤细胞
作者
Kaiyuan Ni,Ziwan Xu,August Culbert,Taokun Luo,Nining Guo,Kaiting Yang,Erik Pearson,Ben Preusser,Tong Wu,Patrick La Rivière,Ralph R. Weichselbaum,Michael T. Spiotto,Wenbin Lin
标识
DOI:10.1038/s41551-022-00846-w
摘要
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-β) 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-β 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.
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