Table 2.

Innovative cathepsin inhibitors targeting the tumor microenvironment.

Drug Name	Target Cathepsins	In Vitro Study	In Vivo Study	Clinical Study	References
ASPER-29	L and S	Inhibits migration and invasion of pancreatic cancer cells.	Inhibits liver and lung metastasis of pancreatic cancer cells in xenotransplantation mouse models.	Not applicable	[182]
AZD7986 (Brensocatib)	C	Not applicable	Suppresses the circulating NETs and alleviates lung metastasis of breast cancer in mouse models.	Phase 3 (bronchiectasis, COVID-19)	[74]
Cycloastragenol (CAG)	B	Not applicable	Synergically reduces the tumor burden by enhancing CD8+ infiltration and cytotoxic activity with anti-PD-1 antibody.	Not applicable	[44]
CLIK-148	L	Inhibits differentiation of functional CD14+ MDSCs.	Reduces tumor growth of breast cancer cells.	Not applicable	[76]
Odanacatib	K	Increases osteoclast fusion and bone resorption.	Synergically reduces tumor size with oxaliplatin in xenograft mouse models of colon cancer cells.	Phase 2 (bone metastasis of breast cancer) Phase 3 (osteoporosis)	[150, 164]
LY3000328	S	Inhibits proliferation of Tregs and increases their apoptosis.	Reduces splenic and intra-tumoral Tregs in mice.	Phase 1	[77]
1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG)	B	Suppresses proliferation and colony formation of colon cancer cells.	Suppresses the ECM remodeling and regulates the populations of T cells, macrophages, and MDSCs, inhibiting liver and lung metastasis in colon cancer-implanted mouse models.	Phase 2 (advanced non-Hodgkin lymphoma, metastatic triple negative breast cancer)	[11]