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.) Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a long-term condition caused by the immune system attacking the gut. Current treatments do not work for everyone and can cause serious side effects. Macrophages are a type of immune cell that normally help heal the gut but become harmful in IBD. This review explains how scientists are trying to reprogram these cells to reduce inflammation and promote healing. We discuss several approaches, including using medicines, nanoparticles, gene editing, and cell therapy. We also highlight the challenges that must be solved before these treatments can reach patients, such as safety, cost, and manufacturing. Understanding these barriers will help guide future research and bring better treatments to people with IBD.