Table 1.

Cathepsins and their role in the tumor microenvironment.

Subtype	Catalytic type	Localizations	Substrates	Roles	Descriptions, References
A	Serine	Ubiquitously	Superoxide dismutase	Inflammation, tissue damage	Mitigates the accumulation of superoxide radicals and prevent inflammation and cardiomyopathy [82].
B	Cysteine	Ubiquitously	Laminin, fibronectin, collagen type 2	ECM degradation	Promotes the ECM remodeling and subsequent metastasis [6, 7, 11].
				Angiogenesis	Enhances MM9 and VEGF secretion [13].
			CXCR3	Impaired chemotaxis	Cleaves and inactivates CXCR3, reducing number of tumor-infiltrating lymphocytes [28].
			CCL20	Induced chemotaxis	Generates a fully-functional CCL20 isoform. [27]
			MHC-I	Impaired antigen presentation	Degrades MHC-I and decreases tumor-antigen presentation [44].
				Autophagy	Regulates autophagy in myeloid cells [57–60, 62].
				Cellular differentiation	M2 macrophage polarization [68, 69].
			TLR-9	Cellular differentiation	Regulates caspase-induced cell death of pro-B cells through TLR-9 signaling [115].
				Fibrosis	Promotes α-smooth muscle actin expression and fibroblast differentiation [157]
				Osteoclastogenesis and bone metastasis	[152]
C	Cysteine	Ubiquitously	PR3, TSP-1	NET formation	Promotes NET formation, and subsequent tumor metastasis [74].
				Cellular differentiation	M1 macrophage polarization [72, 73].
D	Aspartic	Ubiquitously	SPARC	ECM degradation	SPARC fragments promote invasion and migration of tumor cells [3].
			Mucin		Proteolyzes fully glycosylated mucin [10]
				Angiogenesis	Activates VEGF-C and -D [14].
			LDL receptor-related protein 1	Fibrosis	Enhances fibroblast overgrowth, and subsequent tumor progression [23, 24].
				Autophagy	Regulates autophagy in myeloid cells [57, 60].
			C5	Complement activation	Cleaves C5 into C5a, promoting tumorigenesis by stabilizing KCTD5/cullin3/Roc-1 complex [80].
E	Aspartic	Immune cells	TRAIL	Immune cell proliferation	Proteolytically releases soluble TRAIL and activates macrophage-mediated anti-tumor immune response [65].
F	Cysteine	Ubiquitously
G	Serine	Myeloid cells	Fibronectin	ECM degradation	[6, 7]
			MHC-I	Antigen presentation	Upregulates cell surface MHC-I presentation [45, 46].
H	Cysteine	Ubiquitously		NET formation	Composes of NET [75].
K	Cysteine	Osteoclasts Fibroblasts	Elastin and collagen type 1	ECM degradation	[6, 7]
			Notch1 and VEGF	Angiogenesis	Promotes neovascularization to recover from ischemia [15, 16].
			CD18		Facilitates leucocyte recruitment and subsequent IL-1ß-induced angiogenesis [17].
			CCL3, 4, and 21	Impaired chemotaxis Cellular differentiation	Cleaves and inactivates chemokines [26].
					M2 macrophage polarization [70].
			Heparanase	Hematopoiesis and myelopoiesis	Sustains the ECM homeostasis in bone marrow [108, 109].
				Bone metastasis	Increase bone resorption process [150, 151].
			IRS1	Cachexia	Decreases skeletal muscle mass [148].
L	Cysteine	NK cells CD8+ T cells	Fibronectin	ECM degradation	[6, 7]
			ELR chemokines	Chemotaxis	Cleaves and activates the ELR chemokines, contributing to leukocyte recruitment [33].
			C3	Complement activation	Cleave C3 into C3a and C3b, mediating effector T-cell differentiation [78].
			CD1d	Cellular differentiation	Processes CD1d in the thymus, influencing NKT cell selection and maturation [118, 119].
O	Cysteine	Ubiquitously
S	Cysteine	Macrophages, APCs, B cells	Laminin, fibronectin, collagen type 2	ECM degradation	[6, 7]
			Canstatin, arrestatin, and laminin-5	Angiogenesis	Eliminates anti-angiogenic canstatin and arrestatin, and produce pro-angiogenic peptides by cleaving laminin-5 [19].
			Fractalkine	Chemotaxis	Enhances the secretion of fractalkine [30–32].
			(CX3CL1)
			Tumor antigens	Antigen presentation	Enhances tumor-antigen processing and presentation, activating CD4+ T cells and reducing CD8+ T cell infiltration [36, 37, 41].
				Cellular differentiation	M2 macrophage polarization [68].
			JAM-B	Brain metastasis	Degrade a component of blood-brain barrier [154].
V	Cysteine	Thymus, Testis
W	Cysteine	Cytotoxic cells
X	Cysteine	Myeloid cells	Integrin, LFA-1		Activates Mac-1, supporting LFA-1-mediated T cell proliferation and migration as well as phagocytosis in dendritic cells and macrophages [49–51].