Cancer Radiosensitization Nanoagent to Activate cGAS‐STING Pathway for Molecular Imaging Guided Synergistic Radio/Chemo/Immunotherapy

Abstract Immunotherapy has emerged as an innovative strategy with the potential to improve outcomes in cancer patients. Recent evidence indicates that radiation‐induced DNA damage can activate the cyclic‐GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway to enhance the antitumor immune response. Even so, only a small fraction of patients currently benefits from radioimmunotherapy due to the radioresistance and the inadequate activation of the cGAS‐STING pathway. Herein, this work integrates hafnium oxide (HfO 2 ) nanoparticles (radiosensitizer) and 7‐Ethyl‐10‐hydroxycamptothecin (SN38, chemotherapy drug, STING agonist) into a polydopamine (PDA)‐coated core‐shell nanoplatform (HfO 2 @PDA/Fe/SN38) to achieve synergistic chemoradiotherapy and immunotherapy. The co‐delivery of HfO 2 /SN38 greatly enhances radiotherapy efficacy by effectively activating the cGAS‐STING pathway, which then triggers dendritic cells maturation and CD8 + T cells recruitment. Consequently, the growth of both primary and abscopal tumors in tumor‐bearing mice is efficiently inhibited. Moreover, the HfO 2 @PDA/Fe/SN38 complexes exhibit favorable magnetic resonance imaging (MRI)/photoacoustic (PA) bimodal molecular imaging properties. In summary, these developed multifunctional complexes have the potential to intensify immune activation to realize simultaneous cancer Radio/Chemo/Immunotherapy for clinical translation.