Yi Yang, Haiying Zhu
Inflammatory bowel disease (IBD) is sustained not only by dysregulated adaptive immunity, but also by profound disruption of the intestinal macrophage compartment. In healthy mucosa, macrophages maintain immune tolerance, support epithelial integrity, and coordinate repair. In IBD, however, these cells are reprogrammed into heterogeneous pathogenic states shaped by excessive monocyte recruitment, failed acquisition of resident programs, transcriptional and epitranscriptomic rewiring, metabolic stress, and persistent microenvironmental instruction. Macrophage behavior is continuously tuned by microbiota-derived metabolites, dietary signals, and reciprocal crosstalk with epithelial, stromal, and immune cells, placing macrophages at the center of a dynamic inflammatory circuit rather than at the end of a linear effector pathway. This review summarizes how macrophage dysregulation drives core pathological features of IBD, including cytokine amplification, defective microbial handling, epithelial barrier breakdown, fibrosis, and impaired mucosal healing. We further outline the current macrophage-directed therapeutic strategies, including targeted nanomedicine, metabolic reprogramming, biomimetic delivery systems, and vesicle- or gene-based approaches. Although these strategies remain constrained by lesion heterogeneity, incomplete human validation, and translational uncertainty, a more precise understanding of macrophage state architecture may provide a foundation for mechanism-based stratification and precision therapy in IBD.