Hierarchical Core-Shell Nanoplatform with Sequential Mn²⁺/Co²⁺ Release Enables Dual-Track STING Amplification and...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Cancer immunotherapy faces challenges from immunosuppressive tumor microenvironments and hypoxia.
• The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for anti-tumor immunity but is often inefficiently activated in hypoxic tumors.

Purpose of the Study:

• To develop a nanoplatform that synergistically combines radiosensitization with a dual-track STING amplification strategy to overcome tumor hypoxia and enhance cancer immunotherapy.
• To convert "cold" tumors into "hot" tumors, thereby improving treatment efficacy and suppressing systemic cancer progression.

Main Methods:

• Development of a hierarchical core-shell Au@Co-EGCG/Mn-EGCG (ACM) nanoplatform.
• Utilizing the gold core for radiosensitization and catalase-like activity to alleviate hypoxia and generate reactive oxygen species (ROS).
• Hierarchical release of Mn2+ and Co2+ ions to sequentially activate the cGAS-STING pathway, enhancing DNA recognition and STING-cGAMP binding.

Main Results:

• ACM nanostructures effectively alleviate tumor hypoxia, maximize X-ray energy deposition, and induce immunogenic cell death.
• The sequential release of Mn2+ and Co2+ ions creates a synergistic cascade that potently activates the cGAS-STING pathway, leading to increased pro-inflammatory cytokines like IFN-β.
• ACM-mediated radiotherapy achieved in situ tumor ablation and elicited a significant abscopal effect, suppressing distant metastases through enhanced T-cell infiltration and macrophage repolarization.

Conclusions:

• The developed radio-metalloimmunotherapy paradigm effectively overcomes radioresistance and systemic cancer progression.
• This approach transforms resistant microsatellite stable (MSS) colorectal cancers into immune-responsive "hot" tumors.
• The study establishes a new paradigm for converting radiation therapy into a systemic immune adjuvant, offering a translatable strategy for cancer treatment.