Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University of Mainz, Staudingerweg 5, D, 55128 Mainz, Germany.
Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany.
Cells. 2020 Sep 2;9(9):2021. doi: 10.3390/cells9092021.
Cathepsin S (CatS) is a secreted cysteine protease that cleaves certain extracellular matrix proteins, regulates antigen presentation in antigen-presenting cells (APC), and promotes M2-type macrophage and dendritic cell polarization. CatS is overexpressed in many solid cancers, and overall, it appears to promote an immune-suppressive and tumor-promoting microenvironment. While most data suggest that CatS inhibition or knockdown promotes anti-cancer immunity, cell-specific inhibition, especially in myeloid cells, appears to be important for therapeutic efficacy. This makes the design of CatS selective inhibitors and their targeting to tumor-associated M2-type macrophages (TAM) and DC an attractive therapeutic strategy compared to the use of non-selective immunosuppressive compounds or untargeted approaches. The selective inhibition of CatS can be achieved through optimized small molecule inhibitors that show good pharmacokinetic profiles and are orally bioavailable. The targeting of these inhibitors to TAM is now more feasible using nanocarriers that are functionalized for a directed delivery. This review discusses the role of CatS in the immunological tumor microenvironment and upcoming possibilities for a nanocarrier-mediated delivery of potent and selective CatS inhibitors to TAM and related APC to promote anti-tumor immunity.
组织蛋白酶 S（CatS）是一种分泌型半胱氨酸蛋白酶，可切割某些细胞外基质蛋白，调节抗原呈递细胞（APC）中的抗原呈递，并促进 M2 型巨噬细胞和树突状细胞的极化。CatS 在许多实体瘤中过表达，总体而言，它似乎促进了免疫抑制和肿瘤促进的微环境。虽然大多数数据表明 CatS 抑制或敲低可促进抗肿瘤免疫，但细胞特异性抑制，尤其是在髓样细胞中，对治疗效果似乎很重要。与使用非选择性免疫抑制化合物或非靶向方法相比，设计 CatS 选择性抑制剂及其靶向肿瘤相关 M2 型巨噬细胞（TAM）和树突状细胞（DC）成为一种有吸引力的治疗策略。通过优化具有良好药代动力学特征和口服生物利用度的小分子抑制剂可实现 CatS 的选择性抑制。使用功能化的纳米载体可更可行地将这些抑制剂靶向 TAM，以实现定向递送。本文综述了 CatS 在免疫肿瘤微环境中的作用，以及使用纳米载体将强效和选择性 CatS 抑制剂递送至 TAM 和相关 APC 以促进抗肿瘤免疫的最新可能性。
