Single‐Cell Insights Into Macrophage Subtypes in Pulmonary Infections

This review highlights the dynamic plasticity of macrophages during pulmonary infections and proposes an integrative framework defining six functional subtypes: Inflam‐Ms, Hub‐Ms, Reg‐Ms, Prolif‐Ms, Memory‐Ms, and Senesc‐Ms. Single‐cell omics delineate their distinct roles in homeostasis and infection, refining our understanding of macrophage heterogeneity and its implications for infection biology and therapeutic exploration. Abstract Macrophages are pivotal innate immune cells that play essential roles in pathogen recognition, inflammation modulation, and tissue repair during pulmonary infections. Macrophages have remarkable plasticity that is shaped by diverse external stimuli to adapt to the dynamic lung microenvironment. Traditional models of macrophage polarization (M1/M2) cannot capture the full complexity of macrophage heterogeneity and diverse functions during lung infections. Recent advances in single‐cell omics have provided new insights into distinct macrophage subtypes, revealing their unique transcriptional profiles across various stages of infection. This review focuses on the functional plasticity of pulmonary macrophages and how environmental cues modulate their activation and effector functions. An integrative classification framework that defines six major functional macrophage subtypes in pulmonary infections, based on single‐cell omics with functional perspectives is proposed. This framework refines the understanding of macrophage heterogeneity and offers a foundation for developing targeted immunotherapeutic strategies against lung infections. This review highlights the dynamic plasticity of macrophages during pulmonary infections and proposes an integrative framework defining six functional subtypes: Inflam-Ms, Hub-Ms, Reg-Ms, Prolif-Ms, Memory-Ms, and Senesc-Ms. Single-cell omics delineate their distinct roles in homeostasis and infection, refining our understanding of macrophage heterogeneity and its implications for infection biology and therapeutic exploration. Abstract Macrophages are pivotal innate immune cells that play essential roles in pathogen recognition, inflammation modulation, and tissue repair during pulmonary infections. Macrophages have remarkable plasticity that is shaped by diverse external stimuli to adapt to the dynamic lung microenvironment. Traditional models of macrophage polarization (M1/M2) cannot capture the full complexity of macrophage heterogeneity and diverse functions during lung infections. Recent advances in single-cell omics have provided new insights into distinct macrophage subtypes, revealing their unique transcriptional profiles across various stages of infection. This review focuses on the functional plasticity of pulmonary macrophages and how environmental cues modulate their activation and effector functions. An integrative classification framework that defines six major functional macrophage subtypes in pulmonary infections, based on single-cell omics with functional perspectives is proposed. This framework refines the understanding of macrophage heterogeneity and offers a foundation for developing targeted immunotherapeutic strategies against lung infections. Advanced Science, EarlyView.