Specific activation of cGAS-STING pathway by nanotherapeutics-mediated ferroptosis evoked endogenous signaling for boosting systemic tumor immunotherapy

Area of Science:

• Oncology
• Immunology
• Nanotechnology

Background:

• The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for initiating antitumor immunity.
• Specific activation of the STING pathway remains a significant challenge in cancer immunotherapy.

Purpose of the Study:

• To develop a ferroptosis-induced, mitochondrial DNA (mtDNA)-guided nanoplatform (HBMn-FA) for targeted STING pathway activation.
• To enhance STING-based immunotherapy and improve the efficacy of checkpoint blockade therapies.

Main Methods:

• Engineered HBMn-FA nanoplatform to induce ferroptosis in tumor cells.
• Utilized reactive oxygen species (ROS) and Mn2+ to trigger mitochondrial stress and release mtDNA, activating the cGAS-STING pathway.
• Leveraged tumor-derived dsDNA from cell debris to further activate the cGAS-STING pathway in antigen-presenting cells.

Main Results:

• HBMn-FA successfully induced ferroptosis, leading to mtDNA release and cGAS-STING pathway activation.
• The nanoplatform effectively bridged ferroptosis with the cGAS-STING pathway, priming systemic antitumor immunity.
• Demonstrated enhanced therapeutic efficacy of checkpoint blockade in suppressing both localized and metastatic tumors.

Conclusions:

• The developed nanotherapeutic platform offers a novel strategy for specific STING pathway activation in tumor immunotherapy.
• This approach holds promise for overcoming current limitations in STING pathway-targeted cancer treatments.