In HNSCC, spatial profiling shows TLS-rich lymphoid hubs and CD8–cDC1 corridors associate with survival and checkpoint response, whereas continuous SPP1+ TAM–tumor borders and POSTN+ CAF corridors mark immune exclusion and worse outcomes, indicating that topology adds prognostic and pharmacodynamic information beyond bulk composition. This evidence concerns the gene MPPE1 and head and neck squamous cell carcinoma.