M335, a novel small-molecule STING agonist activates the immune response and exerts antitumor effects

Mitochondrial DNA-boosted dendritic cell-based nanovaccination triggers antitumor immunity in lung and pancreatic cancers

“…Our results demonstrated that treatment with DT6066 derived mtDNA or DNA extracted from cNP DT6066 @MV DC not only activated the cGAS-STING pathway in DCs to a greater extent compared to DT6066-derived nuclear DNA ( Figure 7 K) but also enhanced their migration, even when compared to DCs treated with a high dose of the STING agonist DMXAA ( Figures 7 L and 7M). Additionally, FACS analysis showed that treatment with cNP DT6066 @MV DC induced stronger activation of DCs compared to STING agonists such as cGAMP and M335 46 ( Figure 7 N). In summary, these findings elucidate the molecular mechanism through which our cNP cancer cell @MV DC can selectively trigger the activation of endogenous DCs upon reaching intratumoral regions and facilitate their migration to TDLNs probably by activating the mtDNA-cGAS-STING pathway.…”

“… 55 Speculation existed about mtDNA’s higher binding affinity to cGAS compared to nuclear DNA, but evidence was lacking until this study confirmed it. Unlike STING agonists or other STING agonist-loaded nanoparticle, 46 , 56 our approach specifically activates the cGAS-STING pathway in DCs via DC-derived MVs, thereby avoiding potential adverse effects of systemic STING activator administration. 57 …”