Macrophage-directed immunotherapy in Inflammatory bowel disease: advances in reprogramming intestinal phagocytes

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder characterized by dysregulation of the intestinal immune system, in which functional abnormalities of phagocytes such as macrophages play a critical role in pathogenesis. Although conventional therapies such as anti-tumor necrosis factor-α (TNF-α) antibodies are widely used in clinical practice, they have limitations including low response rates and significant side effects, creating an urgent need for novel therapeutic strategies. In recent years, macrophage-directed immunotherapy has emerged as a cutting-edge approach for IBD treatment by reprogramming intestinal phagocytes to restore immune homeostasis. Unlike previous reviews that primarily focus on the M1/M2 polarization framework, this review integrates recent single-cell discoveries of novel macrophage subsets (e.g. SPP1+ and TREM2+ macrophages), systematically examines the crosstalk among signaling, epigenetic, and metabolic regulatory layers, and critically evaluates translational barriers from preclinical models to clinical application. By evaluating preclinical and clinical studies, we assess the potential and challenges of these strategies. Through in-depth analysis, this review aims to provide a theoretical basis for the development of more precise and effective immunotherapies for IBD and to point out future research directions. (Literature search: PubMed, Web of Science, and Embase; January 2000-December 2025.).