Therapeutic potential of inhibitors of gelatinases <scp>MMP</scp> ‐2 and <scp>MMP</scp> ‐9 for the treatment of breast cancer

Matrix metalloproteinases (MMPs) are secreted and cell membrane-associated enzymes that remodel the extracellular matrix (ECM) and cleave extracellular proteins to promote tumor invasion, angiogenesis, immune evasion, and many other aspects of cancer progression. Among this family, the gelatinases MMP-2 and MMP-9, specialized for cleaving collagen IV, are tightly linked to metastatic progression in breast cancer and adverse clinical outcomes. Here, we summarize gelatinase biochemistry and regulation, including zymogen activation, TIMP control, cell-surface trafficking and tethering, and receptor-mediated clearance, and explain how crosstalk between ECM and proteases amplifies invasion and metastatic seeding. We then review therapeutic strategies in two parts: direct inhibition and indirect pathway modulation. Direct approaches emphasize selective small molecules (thiirane mechanism-based inhibitors, allosteric blockers of pro-MMP-9 activation) and protein biologics (monoclonal antibodies, nanobodies, engineered TIMPs). Indirect strategies target upstream signals that drive MMP-2/-9, including MAPK/AP-1, PI3K/Akt/mTOR, NF-κB, EGFR/JAK/STAT, and nuclear receptor and Nrf2/HO-1 programs, with agents that curb invasion, angiogenesis, and metastasis in breast cancer models. Together, these advances define a maturing toolkit for precise gelatinase control and support prospective evaluation in rational combinations to restrain metastatic progression in high-risk breast cancer.