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Cascade STING activation of a ternary immunostimulant for colorectal cancer eradication via photodynamic DNA damage and T regulatory cell inhibition

Yanmei Li,Junmei Nie,Xinyu Li,Ni Yan,Renjiang Kong,Jiaqi Huang,Yeyang Wu,Zhuofeng Li,Yingtao Zhong,Xin Chen,Hong Cheng

Stimulator of interferon genes (STING) plays an essential role in initiating the innate anti-tumor immunity, which could be activated by the cytosolic DNA but suppressed by the immunosuppressive cells. In this work, a self-delivery ternary immunostimulant (designated as ImmSt) is fabricated for colorectal cancer therapy with the immunological cascades of photodynamic DNA damage and T regulatory cell inhibition. Among which, the photosensitizer of Chlorin e6 (Ce6), the STING agonist of 5,6-dimethylxanthine-4-acetic acid (DMXAA) and the phosphatidylinositol 3-kinases (PI3Ks) inhibitor of ZSTK474 could self-assemble into uniform nanomedicine without drug excipient, which enhances the drug stability, bioavailability and pharmacological activities. Importantly, the photodynamic therapy (PDT) effect of ImmSt produces enormous reactive oxygen species to ablate tumor cells, and also triggers the release of cytosolic DNA to amplify the STING signal in combination with the STING agonist. Moreover, ImmSt is able to induce a systemic anti-tumor immunity by the cascade activation of T cells and the decrease of T regulatory cells. In vitro and in vivo results confirm that ImmSt can efficiently eradicate colorectal cancer without severe side effects, which may provide a sophisticated mechanism for immunotherapy in consideration of the immune activation and immunosuppressive factors.