Manganese(ii) complexes stimulate antitumor immunity via aggravating DNA damage and activating the cGAS-STING pathway

Area of Science:

• Immunology
• Oncology
• Biochemistry
• Materials Science

Background:

• The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway is a key target for cancer immunotherapy.
• Developing novel agents that can effectively activate this pathway is crucial for enhancing anti-tumor immune responses.

Purpose of the Study:

• To investigate the potential of novel manganese(II) complexes, MnPC and MnPVA, as activators of the cGAS-STING pathway for cancer treatment.
• To evaluate the chemoimmunotherapeutic efficacy and underlying mechanisms of these manganese complexes.

Main Methods:

• Synthesis and characterization of manganese(II) complexes (MnPC and MnPVA).
• Assessment of DNA-damaging and DNA-repair inhibitory properties of the complexes.
• Evaluation of cGAS-STING pathway activation, cytokine production (type I interferons, TNF-α, IL-6), and immune cell infiltration (dendritic cells, macrophages, cytotoxic T cells) in vitro and in vivo.

Main Results:

• MnPC and MnPVA were found to activate the cGAS-STING pathway.
• The complexes induced DNA damage and inhibited histone deacetylases (HDACs) and poly adenosine diphosphate-ribose polymerase (PARP), leading to cytoplasmic DNA leakage.
• Activation of the cGAS-STING pathway resulted in increased type I interferons, pro-inflammatory cytokines, enhanced immune cell infiltration, and potent anti-tumor activity in vitro and in vivo.

Conclusions:

• Manganese complexes MnPC and MnPVA effectively activate the cGAS-STING pathway, demonstrating significant chemoimmunotherapeutic potential.
• These complexes exhibit enhanced anti-tumor activity compared to Mn²⁺ ions, highlighting their promise as novel cancer treatment agents.