Self-assembled nanomedicine for radiotherapy-activated cascade reactive oxygen species generation to sensitize senescence-based immunotherapy for breast cancer

Although radiotherapy (RT) can induce immunogenic cell death (ICD), the endogenous resistance of tumor cells to X-rays and the immunosuppressive microenvironment has suppressed its therapeutic effect, which can easily lead to tumor recurrence and metastasis after RT. Herein, we prepared a glutathione (GSH)-responsive system called AHD, by loading Aurora-A inhibitor alisertib (Ali) and iron protoporphyrin IX chloride (Hemin), for X-ray-triggered continuous reactive oxygen species (ROS) generation to sensitize breast cancer senescence immunotherapy. AHD accumulates at the tumor tissue through the EPR effect, shows high specificity for the tumor microenvironment with overexpressed GSH, and rapidly releases Ali and Hemin. Under external X-ray irradiation, tumor cells produce H₂O₂, and AHD activates Hemin to catalyze the chemical kinetics process of H₂O₂, continuously generating hydroxyl radicals (•OH).&nbsp;&nbsp; Meanwhile, AHD can also induce tumor cell senescence by up-regulating P21 and P16 expressions. <em>In vitro</em> and <em>in vivo</em> experimental results show that the cascade ROS generation induced by the AHD system can trigger extensive ICD in tumor cells, alleviate the immunosuppressive microenvironment after RT, activate the anti-tumor immune ability of CD8⁺ T cells. Therefore, AHD can be used as a tumor immunomodulator to enhance radioimmunotherapy and has great potential for clinical translation.