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Nat Nanotechnol: Selectively inhibit the cysteine protease in the lysosome of tumor-associated macrophages to improve their ability to cross-present antigens

The activation of CD8+ T cells by antigen cross-presentation is very effective in eliminating tumors. Although this function is traditionally attributed to dendritic cells, tumor-associated macrophages (TAM) can also cross-present antigens. At the same time, TAM is also the most abundant tumor infiltrating white blood cells. TAM is mainly an anti-inflammatory M2 phenotype. It overexpresses growth factors that promote angiogenesis (e.g., vascular endothelial growth factor A), proteases that promote metastasis (e.g., matrix metalloproteinases), and inhibitory molecules (e.g., ARG1, IL). -10 and PDL1) to suppress the adaptive immune response. Consumption of TAM can inhibit tumor growth and metastasis, and high TAM abundance is closely related to the survival rate of patients with many cancer types. This indicates that M2-like TAM may become a promising research target in the development of anti-tumor therapy. However, because the mechanism by which TAM regulates its ability to cross-present antigens is not fully understood, TAM has not been used to activate CD8+ T cells.




Recently, Nature Nanotechnology reported that TAM contains overactive cysteine proteases in its lysosomes, which hinder antigen cross-presentation and thus prevent CD8+ T cell activation. On this basis, the author developed a DNA nanodevice (E64-DNA) targeting mouse TAM lysosomes. E64-DNA can specifically inhibit the cysteine protease population in TAM lysosomes, and inhibit tumor growth by increasing its ability to cross-present antigens to activate CD8+ T cells. In addition, when combined with cyclophosphamide, E64-DNA exhibits the ability to continuously regress tumors in a triple-negative breast cancer model. The DNA nanodevice can target the accuracy of the organelle level, reprogram macrophages, and achieve immune regulation in the body. Unlike DNA nanostructures that deliver therapeutic drugs such as doxorubicin, siRNA or thrombin, these drugs can cause the death of target cells, and the method reported in this article will not eliminate the target cells. Instead, the organelles are reprogrammed, giving it a new and therapeutic property.



The specific mechanism of this therapeutic approach is that E64-DNA is preferentially localized to TAM through receptor-mediated endocytosis and is transported to lysosomes. By inhibiting the activity of cysteine proteases, E64-DNA improves the cross-presentation of antigens in TAM, thereby activating CD8+ T cells to fight tumorigenesis.



Original link:
https://www.nature.com/articles/s41565-021-00988-z
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