Choroidal neovascularization: multipathway pathological mechanisms and novel synergistic therapeutic strategies

Authors:Yao Mudi, Liu Qian, Yan Biao

Corresponding author: Yan Biao, Email: yanbiao@sjtu.edu.cn

Published:2026-09-10

DOI:10.3760/cma.j.cn115989-20251215-00428

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ABSTRACT 

Choroidal neovascularization (CNV) represents a common blinding terminal pathological change across various fundus diseases. Although anti-vascular endothelial growth factor (VEGF) therapy has become the standard of care, long-term clinical practice has revealed significant limitations, including drug resistance, the burden of frequent injections, and the inability to prevent retinal atrophy. These challenges arise primarily due to the fact that CNV is not driven by a single pathway, but is the result of the interaction of multiple pathways involving angiogenesis, chronic inflammation, immune dysregulation, fibrosis, and cellular metabolic reprogramming. Consequently, the therapeutic paradigm is shifting from the sole inhibition of angiogenesis toward the multidimensional reconstruction of tissue homeostasis. This review systematically elucidates the multipathway pathological mechanisms of CNV, with a specific focus on vascular homeostasis (angiopoietin/Tie2, platelet-derived growth factor), inflammation and immune polarization (complement system, NOD-like receptor family pyrin domain containing 3 inflammasome, and immune cell phenotypic transition), fibrosis (epithelial-to-mesenchymal transition, endothelial-to-mesenchymal transition, and macrophage-to-myofibroblast transition), and metabolic reprogramming. Furthermore, emerging therapeutic strategies, including multi-target antibodies, immunomodulators, anti-fibrotic agents, and metabolic interventions, as well as gene and cell replacement therapies, are summarized. Future CNV management will rely on precision phenotyping combined with sequential or synergistic strategies and integrated long-acting delivery technologies. The ultimate goal is to transition from simple VEGF suppression to the active restoration of retinal and choroidal homeostasis, thereby delaying or reversing disease progression.

KEYWORDS：

Choroidal neovascularization;Vascular homeostasis;Metabolic reprogramming;Fibrosis;Multi-target therapy

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Authors Info & Affiliations 

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