These single-cell, chromatin, and spatial layers converge on a reproducible architecture in which ontogeny-defined TAM programs and state-defined tumor programs engage through a limited set of crosstalk axes—CSF1/CSF1R for maintenance and polarization, SPP1–CD44 for mesenchymal reinforcement and perivascular conditioning, and CD47–SIRPα and PD-L1–PD-1 as dominant effector brakes—whose intensity and topology vary by niche. Here, CD44 is linked to neoplasm.