Targeting the Tumor Extracellular Matrix: A New Frontier in Cancer Therapy

The extracellular matrix (ECM) is a dynamic and multifaceted component of the cellular environment, playing a crucial role in regulating cell behavior, tissue architecture, and overall homeostasis. In the context of cancer, the ECM functions far beyond a structural scaffold; it actively contributes to initiation, progression, and metastasis. Aberrant remodelling of the ECM, characterized by altered protein composition, excessive cross-linking, and increased stiffness, disrupts normal cell signaling and promotes malignant transformation through dysregulated mechanotransduction pathways. The extracellular matrix (ECM) within the tumor microenvironment (TME) is dynamically remodeled. Such remodelling helps cancer cells spread, evade the immune system, and become less likely to respond to standard treatment. More evidence suggests that targeting the extracellular matrix or the enzymes that modify it harmfully could be an effective strategy to treat cancer, either on its own or in combination with current cancer treatments. This review examines new approaches to treating cancer that target the extracellular matrix (ECM). These include breaking down tumor-associated ECM with enzymes, inhibiting lysyl oxidase (LOX/LOXL2) activity, normalizing the matrix, creating drug delivery systems that mimic or respond to ECM, and reprogramming cancer-associated fibroblasts (CAFs). This review suggests that combining mechanistic insights with preclinical and clinical evidence can make treatments more effective in aggressive, stroma-rich cancers by selectively targeting tumor-specific ECM abnormalities instead of causing random ECM disruption. This makes drugs work better and restores immune responses that fight cancer.