cGAS–STING innate sensing
cGAS-STING is the cell's alarm for DNA in the wrong place. Radiation, chemotherapy, and ADCs spill DNA into the cytoplasm; cGAS detects it, STING sounds the alarm, and interferon calls in the immune system.
Cytosolic double-stranded DNA (from micronuclei after DNA damage, or from dying tumour cells taken up by dendritic cells) is sensed by cGAS, producing cGAMP, which activates STING on the ER, recruiting TBK1 to phosphorylate IRF3 and NF-κB, driving type I interferon and chemokines (CXCL10) that recruit and prime T cells. Explains the immunogenic effects of radiation (abscopal effect), PARP inhibitors, and TOP1-payload ADCs. Tumours silence STING or express ENPP1 (degrades cGAMP). STING agonists as drugs have disappointed; ENPP1 inhibitors and STING-agonist ADCs are being tested.
In one picture
A smoke detector wired to the fire brigade. DNA in the cytoplasm is smoke; cGAS is the detector; STING is the alarm bell; interferon is the 999 call that brings the immune system. Many tumours have quietly removed the batteries.
Diagram
top- Radiotherapy (especially hypofractionated) + checkpoint inhibitors
- PARP inhibitor + PD-1 combinations
- STING agonists (intratumoural, systemic, antibody-conjugated)
- ENPP1 inhibitors
- TOP1-payload ADCs + IO (ASCENT-04, EV-302 analogues)