TREM2 and SPP1 (osteopontin) are both upregulated in disease-associated microglia, and their crosstalk via DAP12/integrin signaling may gate the full phagocytic transcriptional program. Understanding whether synergy is real (vs additive) determines whether SPP1-integrin antagonism is a viable anti-neuroinflammatory strategy that spares phagocytosis. The challenge requires demonstrating: (1) synergy above additive, (2) molecular mechanism (ITGAV/ITGB3 + DAP12), (3) SPP1 blockade effects on paired phagocytosis vs cytokine outputs. Falsifiable prediction: Simultaneous SPP1 + TREM2-agonist stimulation of iPSC-derived microglia should upregulate phagocytic gene signature (MSigDB GO: phagocytosis) by ≥2.5× vs TREM2-agonist alone (RNA-seq). Anti-integrin αV antibody should reduce IL-6/TNF release by ≥50% without reducing fluorescent bead phagocytic index by >15%, demonstrating pathway separability.