Microglial polarization in retinal neovascularization: Friend or foe?

Retinal neovascularization (RNV) is the central pathological process leading to blindness in ischemic retinal diseases, such as retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Current anti-vascular endothelial growth factor (VEGF) therapies are limited by incomplete responses and substantial injection burdens, highlighting the importance of elucidating novel regulatory mechanisms underlying RNV. As resident immune cells of the retina, microglia play critical yet complex regulatory roles in RNV through functional polarization. Most studies suggest that pro‑inflammatory M1‑like polarization aggravates vascular leakage and pathological neovascular tuft formation by secreting factors such as VEGF, tumor necrosis factor-alpha (TNF‑α), and interleukin-1 beta (IL‑1β). In contrast, reparative M2‑like polarization has been associated with vascular repair and restoration of tissue homeostasis. However, with the application of emerging technologies such as single‑cell transcriptomics, increasing evidence has revealed substantial phenotypic heterogeneity of microglia within the RNV microenvironment, extending beyond the classical M1/M2 dichotomy. Recent findings further indicate that M2-like phenotypes are not invariably protective. Under specific pathological conditions, including chronic hypoxia and oxidative stress, M2-like microglia may promote fibrosis and aberrant vascular remodeling, suggesting that the functional consequences of microglial polarization are highly dependent on the surrounding microenvironment. Therefore, future therapeutic strategies should not simply aim to alter microglial polarization states, but rather selectively target key signaling pathways and functional modules to transform the destructive inflammatory milieu in RNV into a therapeutic environment conducive to vascular repair. Such approaches may provide a theoretical basis for precision interventions in retinal vascular diseases.