Insights Into Macrophage Polarization and M1/M2 Balance in Diabetic Foot Ulcers.

Macrophage polarization, encompassing classically activated (M1) and alternatively activated (M2) states, is a critical determinant of immune response in wound healing. In diabetic foot ulcers (DFUs), a persistent imbalance favoring pro-inflammatory M1 over anti-inflammatory M2 macrophages drives chronic inflammation and impedes tissue repair. This review delineates the central role of macrophage polarization in DFU pathogenesis and systematically summarizes the key signaling pathways that govern this process, including PI3K/AKT, PPARγ, Notch, and Toll-like receptors (TLRs). We further synthesize these cascades into a novel hierarchical network model, identifying NF-κB and JAK-STAT as the core regulatory hubs. Beyond mechanism, we discuss emerging therapeutic strategies-including pharmacological agents and biomaterial-based approaches-that target macrophage polarization, positioning them as promising adjuvants to standard wound care. By integrating mechanistic insights with therapeutic potential, this review provides an updated framework for developing targeted immunomodulatory therapies to break the cycle of non-healing in DFUs.