Manganese(ii) complexes stimulate antitumor immunity via aggravating DNA damage and activating the cGAS-STING pathway. Issue 16 (3rd April 2023)

• Record Type: Journal Article
• Authors: Cai, Linxiang; Wang, Ying; Chen, Yayu; Chen, Hanhua; Yang, Tao; Zhang, Shuren; Guo, Zijian; Wang, Xiaoyong
• Is Part Of: Chemical science. Volume 14:Issue 16(2023)
• Page Start: 4375
• Page End: 4389
• Publication Date: 2023-04-03
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d2sc06036a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Mn complexes act as breakers of DNA to induce DSB, as inhibitors of HDAC and PARP to impede DNA repair, and as activators of the cGAS-STING pathway to trigger immune responses, thereby stimulating T cells to suppress tumor growth in a synergic mechanism. 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 Mn 2+ ions, thus demonstrating great potential as chemoimmunotherapeutic agents for cancer treatment.