STING agonist-loaded cationic radioactive microspheres enhance transarterial radioembolization of hepatocellular carcinoma <i>via</i> tumor immune activation

Hepatocellular carcinoma (HCC) is a severe health condition that poses a significant threat to life, characterized by high incidence and mortality rates. Transarterial radioembolization (TARE) is expected to be a suitable method for the treatment of advanced HCC. Current radioactive microspheres used for internal radiation therapy in HCC treatment suffer from suboptimal embolic effects, a propensity for non-target embolization, and the potential for radiotherapy to adversely impact the tumor immune microenvironment. To address these limitations, we have engineered cationic quaternary ammonium salt-based drug-eluting microspheres capable of loading ¹³¹I and ADU-S100. <i>In vitro</i> and <i>in vivo</i> experiments have confirmed that these microspheres not only exhibit excellent embolic properties but also provide sustained local radiotherapy after drug loading, while concurrently releasing ADU-S100 to activate the STING pathway, which induces a robust CD8⁺ T cell response and enhances the tumor immune microenvironment, resulting in significant therapeutic efficacy against HCC. This approach effectively overcomes the current limitations of poor embolic efficacy and non-target embolization associated with radioactive microspheres. Moreover, it activates the tumor immune microenvironment, addressing the issue of tumor immune resistance and further improving therapeutic outcomes, thereby showing great clinical application potential.