Front Immunol. 2026 Jun 18;17:1855906. doi: 10.3389/fimmu.2026.1855906. eCollection 2026.

ABSTRACT

Pulmonary gas exchange and host defense depend on the dynamic coordination of resident and recruited macrophage populations. Historically, macrophage functions have often been interpreted through the classic M1/M2 dichotomy; however, this binary framework does not capture the heterogeneity and context-dependent plasticity of macrophage states within the lung microenvironment. Advances in single-cell RNA sequencing and spatial multi-omics have substantially refined our understanding of this complex macrophage network. Here, we synthesize evidence from human studies and experimental models to summarize macrophage functional states in homeostasis and across chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, acute lung injury/acute respiratory distress syndrome, and lung cancer. We highlight how macrophage transcriptional programs are shaped by ontogeny, tissue niche, and epigenetic-metabolic regulation, and how these programs are linked to disease-specific remodeling of the pulmonary microenvironment. Across diverse respiratory diseases, persistent tissue injury and microenvironmental stress remodel resident macrophage programs and are frequently accompanied by the expansion and context-dependent differentiation of recruited monocyte-derived macrophages. These macrophage states are associated with inflammatory amplification, epithelial and endothelial barrier dysfunction, extracellular matrix remodeling, and tumor immune evasion. Ligand-receptor and spatial analyses further identify candidate communication axes linking macrophages with stromal, epithelial, endothelial, and immune cells, some of which appear partially conserved across disease contexts. Emerging macrophage-targeted strategies are increasingly being explored beyond broad depletion, with growing interest in context-specific reprogramming and niche modulation, including antibody-based, nanocarrier-mediated, and engineered-cell approaches. Decoding the spatiotemporal trajectories and cell-cell communication networks of specific macrophage subsets, while considering tissue context, species differences, and levels of experimental support, may help clarify mechanisms of tissue remodeling, therapeutic resistance, and macrophage-targeted intervention in complex pulmonary diseases.

PMID:42396453 | PMC:PMC13322945 | DOI:10.3389/fimmu.2026.1855906