期刊
ADVANCED SCIENCE
卷 6, 期 16, 页码 -出版社
WILEY
DOI: 10.1002/advs.201900037
关键词
hypoxia; myeloid-derived suppressor cells; PI3K gamma inhibitor; triggered release; tumor immune microenvironment
资金
- National Basic Research Program of China [2015CB755500]
- National Natural Science Foundation of China [U1401242, 81701817, 81701764, 81571739, 51703257]
- Natural Science Foundation of Guangdong Province [2014A030312018, 2014A010105025, 2017A030310221]
- Guangdong Innovative and Entrepreneurial Research Team Program [2013S086]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017)
- Fundamental Research Funds for the Central Universities [17lgjc01, 17lgpy09]
Hypoxia leads to up-regulation of PD-L1 and decreases T lymphocyte infiltration, thus boosting immunotherapeutic resistance of tumors. Moreover, tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) correlate with potent immune suppressive activity and resistance to the immune checkpoint blocking (ICB) in tumor sites. Here, a multifunctional nanoregulator incorporating MnO2 particles and small molecular IPI549 is developed, which can reshape the tumor immune microenvironment (TIME) to unleash the immune system. The intravenously administered nanoregulator effectively accumulates in tumor sites to alleviate hypoxia via oxygen-generating reduction of MnO2 and to inhibit PI3K gamma on MDSCs via IPI549 release in the tumor microenvironment (TME), which results in concurrent downregulation of PD-L1 expression, polarization of tumor associated macrophages (TAMs) toward pro-inflammatory M1-like phenotype (tumor-suppressive), enhanced infiltration of CD4(+) helper T lymphocytes (Th cells), and cytotoxic CD8(+) T lymphocytes (Tc cells), and suppressed infiltration of regulatory T lymphocytes (T-reg cells) for effective tumor immunotherapy. Furthermore, the local generation of Mn2+ in TME allows tumor-specific magnetic resonance imaging (MRI). More excitingly, the nanoregulator-reshaped TIME is effectively reserved due to the synergistic effect of hypoxia alleviation and MDSC PI3K gamma inhibition, leading to remarkable post-medication inhibition of tumor re-growth and metastasis in an animal study.
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