Extracellular matrices contribute to the inherent immune-suppressive tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC). Tenascin-C, an extracellular matrix protein, is linked to the progression of HNSCC, yet its role in establishing an immune-suppressive TME is unclear. Using a 4NQO-induced model of HNSCC, the authors find that tenascin-C induces an immune-suppressive lymphoid stroma in a CCL21- and CCR7-mediated manner. Tenascin-C expression in the TME allows for the immobilization of CD11c⁺ cells in said tumor stroma, leading to Treg recruitment and establishment of a protumoral TME. Knockout of tenascin-C or CCR7 blockade reduces tumor growth and metastasis. Thus, inhibition of tenascin-C or CCR7 may represent potential treatments for HNSCC patients. To read more, Spenlé and Loustau et al. begins on page 1122. Immunofluorescence staining from the Orend laboratory. Artwork by Lewis Long.