Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery

Abstract

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.

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

“…Ctss is a cysteine protease expressed by diverse immune cells that is responsible for cleaving certain extracellular matrix proteins and cell adhesion molecules to pro-mote immune cell motility [66,67]. In the acute phase after TBI, the upregulation of Ctss expression was mainly observed in microglia; inhibiting Ctss could reduce the level of inflammatory factors, alleviate brain edema, and improve neurobehavioral function [68].…”

Crataegus monogyna and Centella asiatica Extracts as Inhibitors of Cathepsin S

“…The ethanol extract of C. monogyna produced a dose-dependent inhibition of cathepsin S, with a 71.7% maximum inhibition of enzyme activity. Although cathepsin inhibitors, including inhibitors of cathepsin S, have been extensively studied for their anti-inflammatory and anti-cancer properties, very few researchers have investigated medicinal plants used in the treatment of cardiovascular disease for cathepsin S inhibition [25,26]. As one of the few studies on plant extracts or compounds as cathepsin S inhibitors, Hsin et al [27] reported that hispolon isolated from Phellinus igniarius mediated the downregulation of cathepsin S expression and inhibited cell metastasis in cancer cell lines.…”

Overexpression of Lipocalin-2 Inhibits Proliferation and Invasiveness of Human Glioblastoma Multiforme Cells by Activating ERK Targeting Cathepsin D Expression

“…Cysteine cathepsin proteases are degradative enzymes that are involved in lysosomal functions such as protein degradation, autophagy, and cell death. These enzymes are also involved in the features of malignant transformation, including altered adhesion, dysregulated degradation of the ECM, invasion into the vasculature, and distant metastasis [ 30 , 31 ]. CTSD is an aspartic endo-protease that ubiquitously distributed in lysosomes.…”