Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

Objective: Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N‐demethylation.Methods: A single oral 100‐mg dose of sertraline was administered to 6 subjects who were extensive metabolizers and 6 subjects who were poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes were predetermined by polymerase chain reaction–based amplification, followed by restriction fragment length polymorphism analysis. Phenotypes were determined by use of the omeprazole metabolic rate. The plasma concentrations of sertraline and desmethylsertraline were determined by gas chromatography with electron‐capture detection.Results: Six poor metabolizers with m1 mutation had area under the plasma concentration versus time curve (AUC_0‐∞) values (983.6 ± 199.3 μg · h/L versus 697.6 ± 133.0 μg · h/L; P < .05) and terminal elimination half‐life values of sertraline (35.5 ± 5.6 hours versus 23.5 ± 4.4 hours; P < .01) that were significantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozygous for CYP2C19*1. The oral clearance of sertraline in poor metabolizers (105.3 ± 19.4 L/h) was significantly lower than that of extensive metabolizers (148.4 ± 28.6 L/h). The area under the concentration‐time curve from 0 to 144 hours and the maximum plasma concentration of desmethylsertraline in poor metabolizers were significantly lower than the values of extensive metabolizers (627.6 ± 203.8 μg · h/L versus 972.1 ± 270.3 μg · h/L; P < .05; and 23.6 ± 6.5 nmol/L versus 32.4 ± 8.2 nmol/L; P < .01; respectively).Conclusions: The polymorphic CYP2C19 appears to be a major enzyme involved in the N‐demethylation of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of sertraline.Clinical Pharmacology & Therapeutics (2001) 70, 42–47; doi: 10.1067/mcp.2001.116513