Single-cell studies and integrative analyses in HNSCC demonstrate that SPP1+ TAMs engage CD44 and NF-κB–linked pathways, under PI3Kγ–AKT–CREB/STAT3 control, and form reciprocal interactions with SFRP2+ cancer-associated fibroblasts, supporting a pro-invasive ecosystem (44, 45). This evidence concerns the gene SPP1 and head and neck squamous cell carcinoma.