For example, MMP2 and MMP14 are upregulated in a variety of cancer types by TGF-β. Proteases in the cancer microenvironment are considered to be expressed and secreted by the cancer cell as an aspect of aberrant regulation of protease expression. Protease aspects of cancer biology have been investigated for decades, and proteases represent a common target for the development of new anti-cancer therapeutics. Overall, this analysis suggested that MMP2 has the capacity of freeing mutant peptides that could facilitate an anti-tumor response and a better survival rate, and this analysis has the potential of resolving some of the controversy surrounding the role of cancer proteases in cancer progression. Samples representing only MMP2-resistant mutants also represented a worse overall survival. Furthermore, even better HLA class I binders were identified among the samples representing the ECM structural protein mutants resistant to MMP2. The results indicated that tumor samples with mutant amino acids adjacent to the ECM structural protein, MMP2 sites also represented a better survival rate and a larger proportion of mutant peptides with high HLA class I-binding affinities, particularly in comparison with melanoma samples with a reduced or absent T-cell infiltrate. To better understand the potential impact of these mutant amino acids on protease function and cancer progression, we established a bioinformatics approach to assessing the impact of melanoma mutants, among a previously defined set of extracellular matrix (ECM) structural proteins, on the sensitivity of matrix metalloproteinase-2 (MMP2), extensively associated with melanoma. More recently, a very large collection of data regarding mutant amino acids in the potential substrates of cancer microenvironment proteases have become available. Proteases in the cancer microenvironment have been studied for some time, with a general conclusion that such proteases facilitate the spread of cancer, although there is some controversy regarding that conclusion in later-stage cancer development.