Beyond the Binary: Why M1/M2 is Holding Lung Immunology Back

Macrophages are the most abundant immune cell in the lung and play essential roles in tissue development, homeostasis, the initiation of immune responses, and the resolution of injury. Historically, macrophage activation has been defined by the in vitro culture conditions used to generate populations such as M1 or M2, or by the expression of individual transcriptional and cell-surface protein markers. In this Lung Science Brief, we review the historical evolution of macrophage classification and highlight key limitations of conceptual frameworks such as the M1/M2 paradigm for the understanding of lung biology and disease. We argue that comprehensive molecular profiling is a necessary, but not sufficient, starting point for defining lung macrophage subset identities. Meaningful classification schemes for lung monocyte and macrophage subsets should incorporate validation based on functional properties and clinical relevance. We provide examples of approaches to assess lung macrophage function that extend beyond traditional marker-based classification frameworks. Greater emphasis on functional validation may help unify experimental approaches, improve reproducibility, and accelerate translation of macrophage biology into clinical practice.