Immunomodulatory Mechanisms of Chronic Wound Healing: Translational and Clinical Relevance

ABSTRACT Chronic wounds—such as diabetic foot ulcers (DFUs), pressure ulcers (PUs), and venous leg ulcers (VLUs)—pose a serious clinical challenge due to their prolonged inflammatory phase and impaired healing. Increasing evidence reveals that dysregulated immune responses are central to the pathogenesis of chronic wounds. A complex interplay between innate and adaptive immune cells, including macrophages, neutrophils, and T cells, contributes to chronic inflammation, extracellular matrix (ECM) degradation, and tissue repair failure. While current treatments target symptoms, they often overlook the underlying immunopathology. This review provides a comprehensive analysis of the immunomodulatory mechanisms governing chronic wound healing, emphasizing the distinct immune landscapes in DFUs, PUs and VLUs. It explores immunotherapeutic strategies including cytokine‐based therapies, protease inhibitors, and biomaterials with immunoregulatory functions. Special attention is given to the emerging roles of mesenchymal stem cells (MSCs) and MSC‐derived extracellular vesicles (EVs) in modulating inflammation, promoting angiogenesis, and enhancing tissue regeneration. Recent clinical trials of these therapies are also critically evaluated to bridge preclinical findings with translational relevance. By integrating immunology, regenerative medicine, and clinical insights, this review highlights novel targets and strategies for immunomodulation, providing a valuable framework for advancing precision therapies in chronic wound care.