Enzymes in the tumor microenvironment

Enzymes in the tumor microenvironment (TME) comprise a broad and diverse group of biocatalysts secreted by cancer cells, stromal fibroblasts, and infiltrating immune cells that collectively facilitate tumor growth and progression [10, 12, 15]. These enzymes, which include matrix metalloproteinases (MMPs), cathepsins, indoleamine 2,3-dioxygenase (IDO), and carbonic anhydrases, are central to remodeling the extracellular matrix, promoting angiogenesis, and maintaining an acidic, immunosuppressive milieu [2, 6, 16]. By degrading structural proteins or depleting essential nutrients like tryptophan and arginine, they assist in cancer cell invasion and the evasion of host immune responses [6, 10, 11]. Clinically, these enzymes serve as both therapeutic targets for small-molecule inhibitors and as physiological triggers for the localized release of cytotoxic payloads from enzyme-responsive nanocarriers or antibody-drug conjugates [4, 13, 18]. However, therapeutic efforts have frequently been hampered by dose-limiting toxicities, such as musculoskeletal pain, and the significant functional redundancy among different enzyme families within the TME [4, 14].

Other names

TME enzymesTumor-associated enzymesExtracellular matrix remodeling enzymesTumor-secreted proteasesMetabolic enzymes in the TME

Inhibition of specific enzymatic activities to prevent extracellular matrix degradation, block immunosuppressive metabolic pathways (e.g., tryptophan or arginine depletion), or normalize the acidic microenvironment; additionally, these enzymes are utilized as triggers for the localized activation of enzyme-sensitive prodrugs and linkers in antibody-drug conjugates.