Cell Selective STING-Activating Polysaccharide Immunomodulators for Cancer Therapy

Area of Science:

• Immunology
• Oncology
• Materials Science

Background:

• The stimulator of interferon genes (STING) pathway is crucial for reversing tumor-immunosuppressive microenvironment (TIME) in cancer therapy.
• Selective STING activation and its quantitative comparison across heterogeneous cell populations present a significant challenge.

Purpose of the Study:

• To engineer selective STING-activating polysaccharide immunomodulators (SSAPIs) with quantitative activation efficiency across tumor cells, macrophages, and dendritic cells (DCs).
• To utilize dextran as a nanocarrier for improved drug delivery and controlled release kinetics.
• To investigate the impact of different linkers on STING activation selectivity and therapeutic efficacy.

Main Methods:

• Conjugation of the STING agonist (DMXAA) to dextran via ester and disulfide linkers to create SSAPIs (DESX and DSSX).
• In vitro quantitative assessment of STING activation in different cell types.
• In vivo evaluation of antitumor efficacy in B16F10 and CT26 tumor-bearing mice models.

Main Results:

• DESX showed enhanced STING activation in macrophages.
• DSSX demonstrated broad STING activation across tumor cells and immune cells.
• DSSX achieved significant antitumor efficacy, with six out of eight mice showing complete tumor remission, by inducing broad immune responses and reprogramming TIME.

Conclusions:

• Activating the STING signaling pathway across diverse cell populations is critical for effective solid tumor immunotherapy.
• Engineered SSAPIs offer a promising strategy for targeted STING activation and enhanced cancer treatment.
• DSSX, with its disulfide linker, represents a potent immunomodulator for reprogramming the tumor microenvironment.