Immune microenvironment of infantile hemangioma: cellular dynamics, molecular networks, and emerging immunomodulatory...

Infantile hemangioma (IH), the most common vascular tumor of infancy, is characterized by a paradoxical natural history of rapid proliferation followed by spontaneous but often incomplete involution. Although dysregulated angiogenic signaling has long been considered central to IH pathobiology, an angiogenesis-only model is insufficient to explain its phase-dependent behavior, marked clinical heterogeneity, syndromic associations, or variable response to therapy. Emerging evidence instead supports the view of IH as a dynamically remodeled immune-vascular lesion driven by signaling crosstalk among endothelial cells, stem/progenitor cells, stromal elements, extracellular matrix, and immune populations. In this narrative review, we summarize the current knowledge of the immune microenvironment of IH across the proliferative and involution phases, focusing on macrophage polarization, mast cell maturation, dendritic and dendritic-like stromal populations, neutrophil-associated inflammatory signaling, adaptive immune constraints, lymphatic endothelial networks and extracellular matrix remodeling. We further discuss the molecular networks that shape this landscape, including VEGF- and HIF-1α-driven angiogenic programs, metabolic immunosuppression linked to glycolysis and lactate accumulation, and hormonal and immune checkpoint pathways that may contribute to immune tolerance and vascular persistence. Accordingly, we examine the immunological mechanisms of current therapies, particularly propranolol, corticosteroids, and mTOR inhibitiors, and highlight how refractory, segmental, syndromic, or ulcerated IH may reflect distinct immune states. Finally, we outline future directions for mechanism-based treatment, including immune microenvironment reprogramming, metabolic targeting, lesion-confined drug delivery, and biomarker-guided precision stratification. Together, these advances support a transition from empiric vascular suppression toward lesion-targeted immunomodulatory therapy in IH.