Tumor vascular disruption and cGAS–STING activation by gambogic amide-loaded nanomicelles for multiple synergistic treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) continues to significantly threaten human health despite using multiple advanced therapies. The development of simple and effective pharmacologic agents, combined with various available treatments, has the potential to achieve unexpected efficacy. The aim of this study was to develop a gambogic amide coated nanomicelles for the multi-synergistic treatment of triple-negative breast cancer. This study developed PLGA-PEG/GA (PPG) nanoparticles by combining gambogic amide (GA) with polyethylene glycol-grafted poly(lactic-co-glycolic) acid copolymer (PLGA-PEG) for use in synergistic tumor therapies. Intravenous injection of PPG disrupts tumor vasculature and forms blood clots, which in turn mediates photothermal therapy and promotes oxygen release to enhance sensitivity to radiotherapy. More importantly, in addition to starvation therapy that disrupts tumor blood supply, PPG promotes tumor immunogenic death and activates the cGAS–STING pathway, triggering effective systemic anti-tumor immunity. When combined with PD-L1, PPG therapy reduces tumor recurrence. Overall, PPG can synergize with a variety of therapies to activate systemic anti-tumor effects while treating tumors locally.