Proteolysis is essential for tissue homeostasis. Proteolytic factors in the tumor microenvironment have been implicated in tumor development, including tumor growth, local invasion, metastasis, and inflammation. In particular, metalloproteinases, which were first discovered as collagen-degrading enzymes, have been observed to be expressed in various cell populations. Metalloproteinases degrade the extracellular matrix, cytokines, growth factors, and their receptors bound to the cell surface. Tumor cells and various stromal cells produce a large number of metalloproteinases, which contribute to the creation of the tumor microenvironment. This chapter focuses on proteolytic factors, especially metalloproteinase, and describes the relationship between proteolytic factors and the tumor immune microenvironment.