ECM remodeling is indispensable for the formation of desmoplastic regions, and SPP1+ macrophages facilitate ECM organization and cell‒substrate adhesion in POSTN+ fibroblasts by secreting cytokines encoded by MMP1, MMP13, COL1A1 and COL3A1; these findings suggest that the desmoplastic microenvironment of HNSCC is governed by SPP1+ macrophages and POSTN+ fibroblasts. Here, COL3A1 is linked to head and neck squamous cell carcinoma.