Cell Selective STING‐Activating Polysaccharide Immunomodulators for Cancer Therapy

Activation of the stimulator of interferon genes (STING) signaling pathway represents a robust strategy to reverse tumor immunosuppressive microenvironment (TIME) for cancer therapy. However, selective STING activation and its quantitative comparison across heterogeneous cell populations remain a tremendous challenge. Herein, we engineered a type of selective STING-activating polysaccharide immunomodulators (SSAPIs) with quantitative STING activation efficiency across tumor cell, macrophage, and dendritic cell (DC). Dextran as an immune cell targeting nanocarrier was employed to improve drug delivery to macrophage and DC, and to avoid the impact of macromolecular self-assembly on drug release kinetics. The STING agonist (DMXAA) was conjugated to dextran via defined linkers to control the selectivity of STING activation in different cell populations. In vitro experiments quantitively revealed the enhanced STING activation of the ester linker SSAPI (DESX) in macrophage, while the disulfide linker SSAPI (DSSX) prompted STING activation across tumor cell and immune cell. In B16F10 and CT26 tumor-bearing mice models, DSSX exhibited much superior antitumor efficacy with six out of eight complete tumor remission by inducing broad immune responses across diverse cell populations to reprogram TIME. Collectively, this work highlights the significance of activating the STING signaling pathway across cell populations in solid tumor for cancer immunotherapy.