Subretinal fibrosis in neovascular age-related macular degeneration: From clinical features to fibrotic mechanisms and therapeutic opportunities.

Neovascular age-related macular degeneration (nAMD) is a leading cause of irreversible central vision loss worldwide. Although intravitreal anti-vascular endothelial growth factor therapy has substantially improved short-term outcomes, long-term vision is frequently limited by the development of subretinal fibrosis. This progressive scarring process occurs in a substantial proportion of patients and represents a major determinant of permanent visual impairment during long-term follow-up. Subretinal fibrosis arises from a complex interaction among structural injury, inflammatory signaling, and cellular reprogramming. Clinical and imaging characteristics are associated with fibrotic progression. Experimental studies have also provided insights into the underlying biological mechanisms. To organize heterogeneous evidence across clinical, cellular, and experimental studies, this review adopts a dual-axis framework as a working model for subretinal fibrosis in nAMD. The injury-inflammation axis describes processes that establish and maintain a persistent profibrotic microenvironment, whereas the cellular reprogramming axis describes phenotypic transitions of retinal and immune cell types, including epithelial-mesenchymal transition in retinal pigment epithelium cells, macrophage-to-myofibroblast transition, endothelial and pericyte plasticity, and glial remodeling, that may generate or contribute to extracellular matrix -producing effector cell populations. These axes' crosstalk through secretory signaling and matrix-dependent mechanical feedback may contribute to the persistence of fibrotic remodeling. Emerging therapeutic approaches include interventions targeting inflammatory pathways, fibrogenic signaling, and maladaptive cellular reprogramming, including transitions toward mesenchymal and matrix-producing phenotypes, as well as gene-based and bioengineered delivery strategies. This working model may help organize current evidence, identify unresolved causal links, and inform stage-specific therapeutic strategies.