Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising immunotherapeutic strategy for cancer treatment. Manganese(II) complexes MnPC and MnPVA (P = 1,10-phenanthroline, C = chlorine, VA = valproic acid) were found to activate the cGAS-STING pathway. The complexes not only damaged DNA, but also inhibited histone deacetylases (HDACs) and poly adenosine diphosphate-ribose polymerase (PARP) to impede the repair of DNA damage, thereby promoting the leakage of DNA fragments into cytoplasm. The DNA fragments activated the cGAS-STING pathway, which initiated an innate immune response and a two-way communication between tumor cells and neighboring immune cells. The activated cGAS-STING further increased the production of type I interferons and secretion of pro-inflammatory cytokines (TNF-α, IL-6), boosting the tumor infiltration of dendritic cells and macrophages, as well as stimulating cytotoxic T cells to kill cancer cells in vitro and vivo. Owing to the enhanced DNA-damaging ability, MnPC and MnPVA showed more potent immunocompetence and antitumor activity than Mn2+ ions, thus demonstrating great potential as chemoimmunotherapeutic agents for cancer treatment.

This article is Open Access

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