AUTHOR=Temizoz Burcu , Shibahara Takayuki , Hioki Kou , Hayashi Tomoya , Kobiyama Kouji , Lee Michelle Sue Jann , Surucu Naz , Sag Erdal , Kumanogoh Atsushi , Yamamoto Masahiro , Gursel Mayda , Ozen Seza , Kuroda Etsushi , Coban Cevayir , Ishii Ken J. 

TITLE=5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1353336

DOI=10.3389/fimmu.2024.1353336

ISSN=1664-3224

ABSTRACT=<p>5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative—3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9<italic>H</italic>-xanthen-9-one (HHMX)—that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by <italic>STING</italic> gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in <italic>in vitro</italic> experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.</p>