The initial view of the role of MT1-MMP in cancer progression was straightforward: activation of proMMP-2 and degradation of fibrillar collagen to facilitate metastasis. The contributions of MT1-MMP to cancer progression are now viewed as far more complex based on the number of MT1-MMP substrates identified. MT1-MMP activity has a negative impact on immune responses to tumors, and intracellular MT1-MMP activity regulates cancer cell metabolic functions. MT1-MMP has a significant role in angiogenesis, whereby it can exhibit both pro-angiogenic and anti-angiogenic behaviors. These contrasting behaviors point to the importance of the spatial and temporal expression of MT1-MMP. Active MT1-MMP has been found to be highly expressed in stromal cells of the tumor microenvironment (cancer-associated fibroblasts, macrophages, etc.) rather than the tumor epithelium in mouse models of pancreatic and breast cancer. Thus, there are considerations as to how the tumor induces MT1-MMP production. The tumor microenvironment also impacts MT1-MMP activity based on the local pH and oxygen and nutrient content.

Several creative strategies have led to the development of highly selective MT1-MMP activity inhibitors. Of particular interest would be approaches that avoid active site targeting of MT1-MMP, in consideration of prior failures of active site targeting MMP inhibitors in clinical trials. Numerous antibodies have been described that modulate MT1-MMP proteolytic activity by interacting with secondary binding sites (exosites). In a similar fashion, the compound NSC405020 [3,4-dichloro-N-(1-methylbutyl)benzamide] was found to bind to the MT1-MMP HPX domain, inhibit MT1-MMP homodimerization, and reduce tumor size significantly in mouse models. Inhibitors could be designed to disrupt cell surface complexes, such as MT1-MMP association with tetraspanins, the α2β1 and αvβ3 integrins, CD44, and the ternary complex with tetraspanins and the α3β1 integrin. Peptide IS4 (acetyl-VMDGYPMP-NH2), modeled on the region of the MT1-MMP HPX domain that binds CD44 (the outermost strand of blade I), inhibited MT1-MMP-mediated cell migration and metastasis in vivo. CT interactions of MT1-MMP can be inhibited using a peptide model (7R)-CPT (RRRRRRRGRRHGTPRRLLYCQRSLLDKV), resulting in decreased tumor growth. Inhibitors of signaling pathways that impact MT1-MMP function can also be utilized to modulate the enzyme. In order to impact cancer in a positive way, the successful application of these inhibitors will require a thorough consideration of mode of administration (systemic versus topical), mechanism of action (extracellular versus intracellular), cancer stage (pre-metastatic versus metastatic), and potential side effects. It is worth noting that the inhibition of MT1-MMP activity in triple-negative breast cancer mouse models improved tumor profusion and sensitized the tumor to ionizing radiation or doxorubicin treatments.