Manganese-based nano-delivery system for sensitized anti-tumor immunotherapy via combined autophagy inhibition

The stimulator of interferon genes (STING) agonists have been widely applied to active cyclic guanosine monophophate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-STING signaling for tumor immunotherapy. However, the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment (TME). In this study, we constructed a manganese-based nano drug delivery system (NDDS) loaded with hydroxychloroquine (HCQ) for synergistic autophagy inhibition and STING activation-based immunotherapy. Hyaluronic acid (HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis. Subsequently, it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn2+ and HCQ simultaneously. As a kind of STING agonist, Mn2+ can bind to cGAS in tumor cells, activating the cGAS-STING pathway and generating type Ⅰ-interferons (IFN-Ⅰ), which helped alleviate the immunosuppressive TME. Meanwhile, HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation, further sensitizing the cGAS-STING signal. Benefiting from this synergistic mechanism, HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment. Moreover, HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis. This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy. [Display omitted] HA/MnOOH@HCQ can respond to TME degradation to release Mn2+ and HCQ simultaneously. Mn2+ activates the cGAS-STING signal and helps alleviate immunosuppressive TME. Meanwhile, HCQ inhibits autophagy to sensitize cGAS-STING pathway and enhance anti-tumor immunotherapy efficacy.