A biomimetic nanodisc system selectively activates type I interferons by nonclassical STING pathway for cancer immunotherapy

The epigenetic silencing or remarkably diminished expression of STING in cancer cells, along with the structural and functional impairment of the endoplasmic reticulum (ER) and Golgi apparatus, represents a unique mechanism of tumor immune escape and poses an important challenge for STING-targeted therapies. Here, we develop a cell membrane-derived nanodisc system (ND-cGAMP-HP; HP, heparin), which is capable of presenting activated STING proteins in their native form by means of cell membrane-directed display and biological self-assembly techniques. It can directly introduce activated STING protein to tumor cells and circumvent the translocation process between the ER and Golgi apparatus, selectively activating the IFN-I signaling pathway without initiating the inflammation-related pathway NF-κB. ND-cGAMP-HP triggers potent cellular immune responses and remodels the tumor immune microenvironment. Moreover, it augments immune memory by promoting the differentiation of TCF1+ stem cell-like T cells. We thus manifest a strategy based on STING therapy that does not depend on the ER and Golgi apparatus pathways to activate the IFN-I pathway, for cancer immunotherapy. Reduced expression of STING in cancer cells due to ER and Golgi dysfunction enables tumor immune escape and limits STING targeted therapies. The authors here develop a cell membrane derived nanodisc system ND-cGAMP-HP that delivers activated STING directly to tumor cells bypassing ER Golgi translocation which activates the IFN-I signaling pathway and induces potent cellular immune responses.