A guide to the types, structures, and multifaceted functions of matrix metalloproteinases in cancer

Matrix metalloproteinases (MMPs) represent a diverse family of zinc-dependent matrix remodeling enzymes that play critical roles in both physiological and pathological processes, including cancer progression. Their enzymatic activity in matrix remodeling underpins key aspects of cellular physiology; however, uncontrolled remodeling determines several pathological conditions, such as osteoarthritis, fibrosis, and cancer. Several cell functional properties, among them cell proliferation, apoptosis, migration, adhesion, and invasion, are affected by certain MMPs. Moreover, MMPs guide critical steps during cancer progression, including cell behavior, epithelial-to-mesenchymal transition, pre-metastatic niche formation, angiogenesis, and immune surveillance. However, the roles of MMPs in cancer are complex and context-dependent, with certain family members demonstrating opposing functions that vary with tumor stage, anatomic site, enzyme localization, and substrate specificity. These dual roles present both opportunities and challenges for therapeutic targeting and diagnostic applications of MMPs. While early clinical trials of MMP inhibitors (MMPIs) yielded disappointing outcomes, advances in preclinical models have improved our knowledge of MMP biology and continue to inform the design of more effective and selective MMPIs. This guide on the types, structures, and functions of MMPs gives an overview of MMP structural domains, matrix substrates, and specific functions, summarizing their main roles in normal and pathophysiological conditions, with a particular emphasis on cancer progression. New insights into pharmacological targeting, diagnostic applications, and progress on clinical trials are also presented here and critically discussed. This guide revisits the concept of the multifaceted biological functions of MMPs, critically examines the limitations of previous therapeutic attempts, and explores future directions for the development of effective MMP-based molecular targeting.