Abstract
Radiotherapy is widely used for cancer treatment, but its clinical utility is limited by radioresistance and its inability to target metastases. Nanoscale metal-organic frameworks (MOFs) have shown promise as high-Z nanoradiosensitizers to enhance radiotherapy and induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics to synergize with radiotherapy for enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer, GA-MOF, by conjugating a STING agonist, 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), on MOFs for synergistic radiosensitization and STING activation. GA-MOF demonstrated strong anticancer efficacy by forming immune-cell-rich nodules (artificial leukocytoid structures) and transforming them into immunostimulatory hotspots with radiotherapy. Further combination with an immune checkpoint blockade suppressed distant tumors through systemic immune activation. Our work not only demonstrates the potent radiosensitization of GA-MOF, but also provides detailed mechanisms regarding MOF distribution, immune regulatory pathways and long-term immune effects.