In recent years, the tumor microenvironment has gained recognition as a key regulator of cancer progression. A central component of the tumor microenvironment, the extracellular matrix, undergoes dynamic remodeling during tumor development and plays a crucial role in disease pathogenesis. This review highlights the EMILIN/Multimerin family as a paradigm of the extracellular matrix's diverse and complex functions in cancer. Owing to their intricate domain architecture, these proteins engage in multifaceted interactions, not only directly modulating tumor cell proliferation and migration but also influencing other elements of the tumor microenvironment such as blood, lymphatic vessels, and immune cells. The functional landscape of these interactions is further complicated by proteolytic processing, which can both disrupt native functions and generate bioactive fragments with novel biological activities. Importantly, some of these fragments are detectable in biological fluids, suggesting their potential as predictive or prognostic biomarkers and contributing to the advancement of personalized therapeutic strategies.
