We anticipate that HPV-negative tumors with high SPP1-TAM burden and continuous macrophage–tumor interfaces will be candidates for TAM-directed or IL-8–axis combinations layered onto PD-1 regimens, whereas HPV-positive, TLS-rich ecosystems may preferentially benefit from strategies that preserve cDC1 trafficking and enhance dendritic-cell priming (24, 25, 58, 59, 86, 87). This evidence concerns the gene SPP1 and neoplasm.