Reprogramming of radiation-deteriorated TME by liposomal nanomedicine to potentiate radio-immunotherapy.
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ID: 281589
2025
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Abstract
Radiotherapy, although widely used for cancer therapy, always triggers changes in tumor microenvironment (TME) that lead to radioresistance and immunosuppression. In particular, during X-ray irradiation, hypoxia exacerbation would reduce radiosensitivity of tumor cells, while programmed cell death ligand 1 (PD-L1) upregulation impairs antitumor immune responses and exacerbates DNA damage repair, collectively resulting in severe T cell exhaustion and unsatisfactory therapeutic effect. Herein, we developed a liposomal nanodrug, C/J-Lipo, to simultaneously encapsulate a biological enzyme and a bromodomain containing 4 (BRD4) inhibitor for tumor-targeting delivery and TME modulation. Among C/J-Lipo, catalase could catalyze the decomposition of the excess HO in tumors and improve TME oxygenation. Meanwhile, JQ1 as a BRD4 inhibitor after being taken by cancer cells could downregulate PD-L1 expression in both cellular membrane and cytosol, inhibiting PD-1/PD-L1 interaction and DNA damage repair. By alleviating hypoxia and downregulating PD-L1 expression, C/J-Lipo reverses T cell exhaustion in TME. Altogether, C/J-Lipo-based radiotherapy significantly inhibited tumor growth and meanwhile triggered immunogenic cell death (ICD) of cancer cells to activate T cell-mediated anti-tumor immunity. After the combination with αPD-1, C/J-Lipo-based radio-immunotherapy achieved complete tumor eradication and metastases elimination in 80 % mice with survival over 80 days. This multifunctional nanodrug represents a promising strategy to overcome therapy resistance and optimize radio-immunotherapy outcomes.
| Reference Key |
liu2025reprogramming
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| Authors | Liu, Yue; Zhang, Yanxiang; Yang, Xulu; Lang, Shanshan; Zhu, Yansheng; Song, Jiawei; Zhu, Yi; Xu, Haiyi; Pei, Pei; Zhu, Hong; Yang, Kai; Liu, Teng |
| Journal | Journal of controlled release : official journal of the Controlled Release Society |
| Year | 2025 |
| DOI |
10.1016/j.jconrel.2025.113792
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