Masterful macrophages: understanding and targeting activation dysfunction in diabetic wounds

Diabetes mellitus is a group of chronic metabolic diseases worldwide seriously threatens human health and increases social and economic burden; underlying drivers of impaired healing include uncontrolled inflammation, repeated ischemia–reperfusion injury, and neuropathy alongside infection risks. Macrophages orchestrate standard repair, exhibit sustained classical pro-inflammatory activation in diabetes, disrupting growth factor secretion, angiogenesis, and matrix regulation. Hyperglycemia- mediated advanced glycation end products and reactive oxygen species heighten pattern recognition receptor stimulation, causing reduced alternative macrophage differentiation. Promising immunomodulation approaches redirecting their phenotypes to resolve inflammation and stimulate regeneration provides optimism. We discuss macrophage origination, polarization dynamics, diabetic wound phenotypic imbalance, and critical microenvironmental disruptions perpetuating pathological function. Elucidating specific regulatory nodes upholding their activation states will inform intelligent targeting opportunities. Overall, infiltrating macrophages constitute indispensable yet amenable diabetic wound healing coordinators.