Novel APLNR Antagonist Candesartan Induces Tumor Vascular Normalization through ROS/cGAS/STING Axis and Augmented Sunitinib Response in Breast Cancer

Background The tumor vasculature exhibits immature development characterized by inadequate pericyte coverage, resulting in excessive permeability, poor perfusion, and hypoxia. The aberrant vascular network not only facilitates metastasis but also confers therapeutic resistance. Accumulating evidence indicates that inducing tumor vascular normalization represents a promising antitumor strategy. Given the pivotal role of the APLN/APLNR axis in vascular maturation positions it as a promising therapeutic target for anti-tumor vascular therapy.This study aims to discover novel APLNR antagonists, investigate their effects on tumor vascular normalization, and evaluate their combinatorial efficacy with existing anticancer therapies. Methods Initially, based on a drug repurposing strategy, we employed computer-aided virtual screening to identify compounds with high binding affinity to APLNR from the FDA-approved drug library. And further utilized a zebrafish retinal vascular abnormality model to screen out the candidate compound that could induce vascular normalization. Then, we assessed the impact of the candidate compound on vascular normalization by detecting the proliferation, migration and tubule formation abilities of HUVEC in vitro and investigating tumor vascular maturity, vascular perfusion and hypoxia in vivo . Additionally, we explored the molecular mechanisms underlying the regulation of vascular normalization by the candidate compound using western blot and comet assay. Finally, we employed a breast cancer mouse model to examine the antitumor efficacy of the candidate compound when used alone or in combination with Sunitinib. Results Employing a drug repurposing strategy combined with computational screening, we identified Candesartan, an approved antihypertensive drug with a well-established safety profile, as a high-affinity APLNR antagonist. Additionally, in vitro, Candesartan significantly inhibited HUVEC proliferation, migration, and tube formation. In vivo, it promoted tumor vascular maturation, improved vascular perfusion, and alleviated hypoxia. Mechanistically, Candesartan activated the ROS/dsDNA/cGAS/STING pathway to drive vascular normalization. Notably, Candesartan synergistically potentiated sunitinib’s antitumor efficacy while inhibiting pulmonary metastasis and ameliorating Sunitinib-induced hepatotoxicity. Conclusion This study provides a novel direction for APLNR antagonist development and demonstrates that combining Candesartan with the standard antiangiogenic agent Sunitinib leverages the advantage of drug repurposing, suggesting a promising and rapidly translatable strategy for optimized cancer therapy.