期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-020-20723-x
关键词
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资金
- National Key R&D Program of China [2020YFA0710700, 2018YFA0208900]
- National Natural Science Foundation of China [81974459, 81627901, 81773653, 81672937]
This study demonstrates that metformin-loaded mannose-modified macrophage-derived microparticles can reprogram the tumor immune microenvironment, enhance responses to anti-PD-1 therapy, and promote infiltration of CD8(+) T cells into tumor tissues.
The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8(+) T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8(+) T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy. Durable response rate to anti-PD-1/PD-L1 therapy remains relatively low in patients with cancer. Here the authors show that metformin-loaded mannose-modified macrophage-derived microparticles reprogram the tumor immune microenvironment and improve responses to anti-PD-1 therapy.
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