A Multidimensional Framework for Interpreting Macrophage Markers in the Era of Cellular Heterogeneity

ABSTRACT Macrophages display remarkable heterogeneity across tissues and disease contexts, challenging their definition based on molecular markers. Although widely used, many macrophage markers are neither specific nor stable and often reflect context‐dependent activation states rather than cell identity. Here, we propose a multidimensional framework in which macrophage markers are interpreted as context‐dependent readouts of macrophage biology across orthogonal dimensions. This framework integrates lineage, identity, and functional state with distinct measurement modalities, including surface, transcriptomic, and metabolic features. By organizing and contextualizing established and emerging macrophage markers within this framework, we provide a practical strategy to interpret macrophage heterogeneity and infer cellular origin and functional states from marker combinations. This approach reconciles diverse macrophage populations across tissues and disease settings and offers a unifying framework for the interpretation of macrophage markers.