Tumor Vascular Destruction and cGAS‐STING Activation Induced by Single Drug‐Loaded Nano‐Micelles for Multiple Synergistic Therapies of Cancer

Abstract Cancer and its metastasis/recurrence still threaten human health, despite various advanced treatments being employed. It is of great significance to develop simple drug formulations to enhance the efficacy and synergistic integration of various monotherapies. Herein, DMXAA, a vasodestructive agent with cGAS‐STING stimulation capacity, is integrated with polyethylene glycol grafted poly (lactic‐ co ‐glycolic) acid co‐polymer (PLGA‐PEG), obtaining PLGA‐PEG/DMXAA (PPD) nanoparticles to induce the tumor‐specific vascular destruction for multiple synergistic therapies of cancer. PPD could induce the formation of blood clots in the tumor after intravenous injection, which subsequently mediate photothermal therapy and further promote the release of oxygen for enhanced radiotherapy. Meanwhile, the enhanced vascular injury can induce perfect starvation therapy of tumor. More importantly, PPD‐mediated therapies could trigger potent systemic anti‐tumor immunity via inducing the immunogenic death of tumor cells and activating the cGAS‐STING pathway. Together with anti‐PD‐L1, PPD‐mediated therapies could not only remove the primary tumors, but also effectively eliminate the distant tumors, metastasis, and recurrence. Therefore, the modulation of tumor composition induced by a single drug‐loaded nano‐micelle could be utilized to enhance the therapeutic effect of multiple treatments for synergistic and systemic antitumor response, providing a practical strategy for cancer therapy.