How microenvironmental factors such as skin extracellular matrix (ECM) and resident immune cells contribute to cutaneous T-cell lymphoma (CTCL) is not well understood. Here we report a ligand-receptor interaction connecting the ECM and immunosuppressive macrophages in the CTCL microenvironment. We find that expression of a fibronectin splice variant encoding extra domain A (EDA), a hallmark of ECM dysregulation in cancer, occurs in human CTCL lesions and in mouse CTCL tumors. Notably, EDA is a ligand for toll-like receptor 4 (TLR4), a pattern recognition receptor with roles in regulating immunity within tumor microenvironments. We find that CD206+ immunosuppressive macrophages within the lesional skin of CTCL patients express high levels of TLR4. Similarly, tumor-localized CD206+ macrophages are TLR4-high in our immune-competent CTCL mouse model. Lastly, we observe the abrogation of CTCL tumor growth in TLR4 deficient mice compared to wild type. Together, these data suggest that TLR4 activity in the CTCL microenvironment promotes tumor growth, and EDA-TLR4 interactions may drive immunosuppressive macrophages. Our results uncover a link between the extracellular matrix and anti-tumor immune response that may reveal new therapeutic targets in CTCL.