Dual-pathway STING activation and chemodynamic therapy for improved anti-tumor therapy

The cyclic-GMP-AMP synthetase stimulator of interferon genes (cGAS-STING) pathway is a naturally occurring immune pathway activated by cytosolic DNA. The end products of this pathway are type I interferon (type I IFN) and multiple cytokines, which have been utilized to carry out anti-tumor therapy in recent years. However, human embryonic growth factor receptor-2 (HER2), which is highly expressed in a variety of tumor cells, can inhibit the cGAS-STING pathway through phosphorylation, seriously interfering with the normal expression of this pathway. Therefore, if HER2 inhibition is not taken into account when activating the cGAS-STING pathway, the effectiveness of the STING pathway will be greatly reduced. Herein, we developed a nanosystem hMnOx-LPT@BSA (HMLB) with STING pathway activation for overcoming tumor suppression and enhancing immune response. In the presence of glutathione (GSH), honeycomb MnOx (hMnOx, HM) degraded and released a large amount of Mn2+, which could not only produce reactive oxygen species (ROS) to kill tumor cells through a Fenton-like reaction but also bind to STING pathway components to improve cytosolic DNA detection. In response to the high expression of HER2 in tumor cells, the HER2-specific inhibitor Lapatinib (LPT) was introduced to promote cGAS-STING pathway-based immunotherapy together with Mn2+. The synergistic effect of the dual approach activation of the STING pathway and Mn2+-dependent chemodynamic therapy (CDT) could achieve the goals of inhibiting tumor growth and inducing immune responses. Therefore, we believe that this therapeutic strategy has a promising potential for further clinical translation.