Research advances in the translational application of anti-VEGF combined with subthreshold micropulse laser therapy for refractory diabetic macular edema.

Diabetic macular edema (DME) is a leading cause of visual decline in patients with diabetic retinopathy (DR). While intravitreal anti-vascular endothelial growth factor (VEGF) agents have become the first-line treatment, some patients fail to achieve complete resolution or experience recurrent fluid accumulation despite ongoing treatment regimens. This therapeutic resistance defines the difficult entity known as refractory DME, which remains a significant management dilemma in clinical practice. Subthreshold micropulse laser (SML) selectively targets retinal pigment epithelium (RPE) cells, inducing heat shock protein (HSP) expression and modulating inflammatory cytokine release. It exerts a biomodulatory effect while avoiding the photocoagulation scars associated with conventional laser. Translational research on combining anti-VEGF therapy with SML has attracted increasing attention. This narrative review covers the disease characteristics and treatment dilemmas of refractory DME, the therapeutic mechanism of SML, clinical evidence for combination therapy, and related translational research. Future directions, including optimization of individualized treatment strategies and exploration of novel biomarkers, are also discussed.