Macrophage polarization as a therapeutic target in lung diseases: From pathogenesis to precision intervention.

Macrophages serve as core effector cells of the innate immune system, exerting dual regulatory roles in pulmonary homeostasis maintenance and disease pathogenesis. Pulmonary macrophages comprise two distinct ontogenetic populations: self-renewing tissue-resident alveolar macrophages and monocyte-derived recruited macrophages under inflammatory conditions. Both populations exhibit remarkable phenotypic and functional plasticity, transitioning between pro-inflammatory and anti-inflammatory/reparative states in response to microenvironmental stimuli. Critically, this polarization process is precisely orchestrated by an intricate regulatory network encompassing TLR4/NF-κB, JAK/STAT, PI3K/Akt, Notch, and TGF-β/Smad signaling pathways, and the functional imbalance of macrophage polarization is a central mechanism underlying the initiation and progression of various pulmonary diseases. This review systematically delineates the ontological heterogeneity of tissue-resident versus recruited pulmonary macrophages and the molecular basis governing their polarization. We subsequently emphasize the pivotal role of macrophage functional dysregulation in the pathogenesis of major pulmonary diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and lung cancer. Building upon this foundation, we comprehensively summarize advances in therapeutic strategies targeting polarization-critical molecules, modulating signaling pathway activity, and intervening in metabolic reprogramming for pulmonary disease treatment. Furthermore, we critically discuss the paradigm shift from non-specific broad-spectrum modulation to targeted precision reprogramming, highlighting the integration of advanced analytical platforms such as single-cell multi-omics and spatial transcriptomics, coupled with dynamic monitoring technologies, to achieve spatiotemporal regulation of macrophage function. Notably, we propose an innovative framework integrating artificial intelligence-driven predictive modeling with macrophage-derived exosome biomarker discovery, enabling real-time non-invasive monitoring of polarization dynamics and facilitating adaptive therapeutic decision-making. Through in-depth understanding of macrophage functional plasticity and its regulatory mechanisms, this article proposes an evolving strategic framework transitioning from antagonistic intervention towards immune homeostasis reconstruction, providing novel theoretical underpinnings and translational research directions for precision immunotherapy in refractory lung diseases.