A nanoplatform integrating sonodynamic and manganese to enhance tumor immunotherapy via synergistic activation of the cGAS-STING pathway

The crucial role of the cGAS-STING pathway in activating innate immunity has drawn considerable attention in tumor immunotherapy. However, exogenous agonists such as cyclic dinucleotides exhibit limitations in stability and targeting. Inducing the generation of endogenous double-stranded DNA (dsDNA) represents a promising strategy for activating the cGAS-STING pathway. In contrast, Mn2+ activates cGAS independently of dsDNA and thus provides a complementary approach. This study reports a nanoplatform that integrates sonodynamic therapy (SDT) with manganese to enhance tumor immunotherapy through synergistic activation of the cGAS-STING pathway. This nanoplatform utilizes polymer nanoparticles for the co-delivery of Chlorin e6 and MnO2 nanoparticles. Reactive oxygen species (ROS) produced during SDT activate the cGAS-STING pathway through targeted induction of endogenous DNA damage. This activation is further enhanced by MnO2, leading to enhanced dendritic cell maturation and T lymphocyte infiltration. Additionally, MnO2 nanoparticles continuously generate oxygen at the tumor site, improving SDT efficacy and reducing immunosuppression by down-regulating HIF-1α. Pyroptosis induced by SDT also contributes to the enhancement of anti-tumor immunity. As a result, the nanoplatform not only inhibits tumor growth of 4T1 tumor-bearing mice but also prevents tumor recurrence by establishing long-term immune memory. This nanoplatform provides an effective strategy for tumor immunotherapy.