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

Abstract

Activating the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway is a promising immunotherapeutic strategy for cancer treatment. Manganese(II) complexes MnPC and MnPVA (P = 1,10-phenanthroline, C = chlorine, and 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 and 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 in 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.