Transformation of the extracellular matrix during uveal melanoma development, progression, and at the hepatic metastatic niche.

The tumour microenvironment comprising tumour cells, immune infiltrates, stromal components, and the extracellular matrix (ECM) plays a central role in cancer biology, modulating key hallmarks, such as proliferation, immune evasion, and metastasis. The ECM is a dynamic network of collagens, elastin, glycoproteins, and proteoglycans and emerging evidence highlights its role in tumour progression, with loss of matrix organisation altering tumour cell behaviour through both pro- and anti-tumourigenic mechanisms. Uveal melanoma (UM), the most common primary intraocular malignancy in adults, carries a poor prognosis due to its propensity for hepatic metastasis and limited therapeutic options. The uveal tract, comprising the choroid, ciliary body, and iris, relies on highly specialised ECM architectures, and we describe in this review how they support nutrient exchange, lens accommodation, and light regulation while mediating essential biochemical and biomechanical signalling. Understanding this baseline ECM is essential for interpreting the pathological matrix remodelling that occurs in UM. We describe marked compositional differences in ECM between low- and high-metastatic risk primary UM, revealing key mechanisms of tumour progression, including upregulation of structural collagens, fibronectin, laminins, and ECM-remodelling enzymes that activate oncogenic signalling pathways enhancing proliferation, invasion, and metastatic competence. We also explore the hepatic metastatic niche, where stellate cell-driven ECM remodelling promotes a fibrotic, immune-restrictive microenvironment that limits therapeutic efficacy. Finally, we discuss experimental constraints limiting ECM research and highlight advances in decellularised scaffolds, three-dimensional culture systems, and multi-omics technologies to dissect tumour-matrix interactions and uncover ECM-targeted therapeutic vulnerabilities with the potential to improve UM's poor clinical outcomes.