(A) Activation of the cGAS/STING pathway can be triggered either through the importation of cGAMP or the presence of double-stranded DNA (dsDNA). Activated cyclic GMP-AMP synthase (cGAS) uses ATP and GTP to catalyze the formation of cGAMP that binds to STING localized on the ER membrane. STING then recruits TBK1, which activates/phosphorylates IRF3 and NF-κB, which translocates to the nucleus, thereby inducing the transcriptional activation of proinflammatory interferon responses. (B) A variety of therapeutics are being evaluated in clinical trials, such as cyclic dinucleotides or STING agonists that can trigger the activation of cGAS/STING pathway. The STING signal is terminated (denoted by the X) when activated STING in the ER-Golgi compartment binds to LC3 on the autophagy membrane, leading to the degradation of STING and the associated cytoplasmic DNA in the autolysosome. Excess intracellular cGAMP is transported out of the cell and hydrolyzed by ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) to yield AMP and GMP. ENPP1 inhibitors maintain proinflammatory cGAMP concentrations. ERGIC; endoplasmic-reticulum-Golgi intermediate compartment.