Therapeutic Targeting of Collagen Biosynthetic Enzymes in Cancer

Abstract

The dynamic interplay between collagen and diverse cell types within the tumor microenvironment (TME) plays a critical role in tumor progression, drug resistance and metastasis. Dysregulated collagen biosynthesis, aberrant post-translational modifications of collagen, and excessive collagen deposition drive extracellular matrix (ECM) remodeling and promote tumor progression. Aberrant expression and activity of collagen-modifying enzymes, including prolyl-4-hydroxylases (P4Hs), procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs), and lysyl oxidase (LOX) across cancer subtypes contribute to tumor stiffness, angiogenesis, invasion, metastasis, and therapeutic resistance. Additionally, emerging evidence suggests that collagen-modifying enzymes represent attractive targets for cancer therapy. Therefore, this review examines the molecular mechanisms underlying the roles of these enzymes in cancer progression, with particular emphasis on matrix cross-linking, hypoxic adaptation, and metastatic dissemination. It also highlights recent advances in the development of inhibitors targeting collagen-modifying enzymes, along with their therapeutic potential, challenges in clinical translation, and opportunities for combination strategies. Targeting the collagen-modifying enzymes offers promising avenues for disrupting the TME and improving cancer treatment outcomes. Furthermore, understanding the interplay between collagen-modifying enzymes and cancer progression will open novel avenues for developing targeted therapies aimed at disrupting the TME and improving patient outcomes.