BAF312 Inhibits the Growth of Glioma and Promotes the Normalization of Tumor Blood Vessels

ABSTRACT This study investigates the repurposing of BAF312 (Siponimod), an FDA‐approved sphingosine‐1‐phosphate (S1P) receptor agonist for multiple sclerosis, as a dual‐targeting therapeutic agent for glioma by inhibiting tumor growth and normalizing aberrant tumor vasculature. The clinical correlations between S1PR1/5 expression and glioma prognosis were analyzed using the GEPIA and HPA databases. The effects of BAF312 on tumor growth, cell cycle progression, apoptosis, and vascular remodeling were evaluated using orthotopic GL261 glioma models and glioma cell lines (U118MG, T98G, GL261). Techniques such as bioluminescent imaging, flow cytometry, Western blot analysis, and immunofluorescence staining were employed. High expression of S1PR1/5 was associated with improved survival in glioma patients. BAF312 inhibited glioma proliferation both in vitro and in vivo by arresting the G1‐S transition through modulation of the Skp2‐p27 axis and inducing apoptosis through p53‐independent mitochondrial pathways. Additionally, BAF312 promoted tumor vascular normalization by enhancing pericyte coverage (PDGFRβ + ), reducing vessel leakage (TER119 + RBCs), and altering vessel diameter distribution. Notably, BAF312 reduced CD8 + T cell infiltration, suggesting that its efficacy is predominantly mediated by tumor‐intrinsic mechanisms. BAF312 exhibits significant anti‐glioma activity through mechanisms involving cell cycle arrest, apoptosis induction, and vascular normalization, highlighting its potential as a repurposed therapeutic agent. This study offers preclinical evidence supporting the anti‐glioma effects of BAF312; though further investigation is warranted to evaluate combinatorial efficacy with conventional therapies and address immunosuppressive effects limiting monotherapy application.