Monocyte Phenotypic Plasticity in Peripheral Artery Disease: From Pathophysiology to Therapeutic Targets

Peripheral artery disease (PAD) remains a significant global health issue, with current treatments primarily focused on relieving symptoms and addressing macrovascular issues. However, critical immunoinflammatory mechanisms are often overlooked. Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development, affecting atherogenesis, plaque progression, ischemia-reperfusion injury, and chronic ischemic remodeling. This narrative review aims to summarize the latest advances (2023–2025) in understanding monocyte diversity, functional states, and their changes throughout different stages of PAD. We discuss both established and emerging biomarkers, such as circulating monocyte subset proportions, functional assays, immune checkpoint expression, and multi-omics signatures, highlighting their potential for prognosis and the challenges in translating them to clinical practice. We also present a stage-specific approach to mapping out potential therapies, linking monocyte phenotypes to molecular targets and possible interventions. Additionally, we address regulatory, economic, and implementation considerations for applying these findings in a clinical setting. The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.