Stimulator of
interferon genes (
STING) is a mediator of immune recognition of cytosolic
DNA, which plays important roles in
cancer, cytotoxic
therapies, and
infections with certain pathogens. Although pharmacologic
STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic
biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic
STING agonists are yet to be described. We investigated whether systemic
STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic
STING agonists and imaged with
18F-FDG PET after 24 h. Splenocytes were harvested 6 h after
STING agonist administration and analyzed by single-cell
RNA sequencing and flow cytometry.
18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from
STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or
pancreas cancer tumors, the effects of
STING agonist treatment on
18F-FDG uptake, T-lymphocyte activation marker levels, and
tumor growth were evaluated. Results: Systemic delivery of structurally distinct
STING agonists in mice significantly increased
18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in
STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic
STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In
tumor-bearing mice,
STING agonist administration significantly delayed
tumor growth and increased
18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between
STING signaling and immunometabolism and suggest that
18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic
STING agonists at a whole-body level and guiding their clinical development.