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

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 (HfO₂) nanoparticles (radiosensitizer) and 7-Ethyl-10-hydroxycamptothecin (SN38, chemotherapy drug, STING agonist) into a polydopamine (PDA)-coated core-shell nanoplatform (HfO₂@PDA/Fe/SN38) to achieve synergistic chemoradiotherapy and immunotherapy. The co-delivery of HfO₂/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 HfO₂@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.