Decoding macrophage heterogeneity in the pulmonary fibrosis lung cancer transition

Pulmonary fibrosis (PF) significantly increases the risk of lung cancer (LC), but the mechanisms underlying this transition remain unclear. This overview positions macrophage heterogeneity as a central node within the PF-LC continuum. First, we describe important subpopulations of profibrotic and pro-tumor macrophages, including SPP1+, MERTK+, TREM2+, and MARCO+ cells, using high-resolution spatial and single-cell omics technologies. Next, we analyze the fundamental mechanisms that determine their function: the fibrotic microenvironment (e.g., extracellular matrix stiffness, hypoxia) induces profound metabolic reprogramming (e.g., Warburg effect, lipid peroxidation) and stabilizes epigenetic memory (e.g., DNA methylation, histone modifications), locking them into a pathogenic state. This reprogramming occurs through two main pathways: (1) metabolic reprogramming, characterized by aerobic glycolytic conversion and dysregulated lipid metabolism, which stimulates both pathogenic functions and suppression of T cell activity; (2) Epigenetic modifications, including stabilized alterations in DNA methylation, histone modifications, and superactivator patterns, which maintain cells in a tumor-promoting phenotype. As central nodes of communication, these macrophages interact pathologically with fibroblasts and epithelial cells through secreted factors and extracellular vesicles, forming self-reinforcing feedback loops that promote disease progression. We are studying the crucial role of new technologies, particularly multi-omic spatial models and high-precision organoids, in fostering mechanistic discoveries. These discoveries pave the way for new macrophage-focused therapeutic strategies, including the precise stratification of patients using biomarkers from liquid biopsies (such as soluble SPP1 and MARCO) and the development of targeted drug delivery systems for the selective modulation of macrophage function, thus establishing a new paradigm for therapeutic interventions in pulmonary fibrosis with concomitant lung cancer.