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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 (18)F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. (18)F-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 (18)F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased (18)F-FDG uptake in the spleen. The average spleen SUV(max) 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 (18)F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that (18)F-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.

Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer (68)Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of (68)Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial (68)Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUV(max)/organ SUV(mean)). Results: At all time points, average SUV(max) was highest in the liver. Tumor and organ SUV(mean) decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E−03 mSv/MBq), followed by ovaries (1.15E−03 mSv/MBq) and red marrow (8.49E−04 mSv/MBq). The average effective total-body dose was 7.80E−03 mSv/MBq. Conclusion: (68)Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of (68)Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

The effects of exercise training and iron intake on iron metabolism in adult female rats were investigated. Adult female Sprague-Dawley rats were assigned to either an exercise (E) or sedentary (S) group and fed either a diet containing 9 ppm (9) of dietary iron (low iron level), or 40 ppm (40) of iron (a level slightly above the National Research Council recommendations). The exercise animals were subjected to a program of swimming, 5 days/week, over a 6- week period. Total food intake and final body weight were similar between the E and S groups. In both 40-E and 9-E animals, concentration of serum iron was significantly (P