Impaired Macrophage Efferocytosis: Shared Mechanisms and Therapeutic Implications in Immune-Mediated Inflammatory Diseases

Abstract: Efferocytosis, the specialized phagocytic clearance of apoptotic cells, is a fundamental mechanism for maintaining tissue homeostasis and immune tolerance. Among professional phagocytes, macrophages play a central role due to their high plasticity and tissue-resident properties. By recognizing and engulfing apoptotic cells through a repertoire of receptors and bridging molecules, macrophages prevent secondary necrosis and inflammation and actively shape the local immune microenvironment via metabolic and epigenetic reprogramming. Defective efferocytosis has been increasingly implicated in the pathogenesis of immune-mediated inflammatory diseases (IMIDs), including systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, inflammatory bowel disease, psoriasis, atopic dermatitis, and autoimmune liver diseases. Impairments in efferocytosis trigger persistent inflammation, autoantigen exposure, and tissue damage, thereby fueling chronic disease progression. Recent mechanistic studies highlight the dysregulation of TAM receptors, bridging molecules, and intracellular signaling pathways as critical determinants of efferocytosis dysfunction in IMIDs. In this review, we propose defective macrophage efferocytosis as a shared pathogenic mechanism across diverse IMIDs and integrate emerging evidence linking efferocytosis to immunometabolic and epigenetic rewiring in chronic inflammation. We further discuss therapeutic strategies targeting efferocytosis pathways and highlight key translational challenges and opportunities. By positioning efferocytosis as a central pathogenic node and a readily targetable mechanism across the spectrum of IMIDs, this review offers a conceptual framework that links fundamental mechanistic insights with clinical translation, thereby laying the groundwork for precision immunomodulatory strategies that aim to restore immune homeostasis rather than merely suppress inflammation. Keywords: macrophage efferocytosis, immune-mediated inflammatory diseases, TAM receptors, apoptotic cell clearance, inflammation resolution