How DNA activated GAS-STING linked to immunotherapy efficiency

Cancer treatment results in release of damaged DNA into the cytosol which activates cGAS-STING signaling but limited success has been achieved  to exploit this pathway to improve immunotherapy.

Ther authors shoe that the cytosolic DNA exonuclease TREX1 chews up DNA but is degraded by the E3 ubiquitin ligase SPOP. TREX1 is stabilized by the deubiquitinase USP7.

The researchers show that cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and suppressing cGAS-STING-mediated immune activation.

Targeting USP7 enhances the effectiveness of radiotherapy combined with immune checkpoint blockade, providing a new strategy to overcome resistance and improve therapy outcomes.

https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00547-1

https://sciencemission.com/Ubiquitination-directed-cytosolic-DNA-degradation