Solid tumors remain a clinical challenge due to the complexity of the tumor microenvironment (TME) and high variability of immune responses to treatment. Monitoring immunological activity within the TME has emerged as a critical determinant of tumor progression and therapeutic outcome. With the advent of radiotracers that can non-invasively visualize immunological activity, research interest has grown in their potential to enhance precision oncology and support adaptive clinical decision-making. Among these, metabolic positron emission tomography (PET) imaging with ¹⁸FF-AraG, a fluorine-18-labeled guanine nucleoside analog, offers a promising functional approach for visualizing activated T-cells by leveraging their unique mitochondrial nucleotide salvage pathways. Unlike antibody-based immuno-PET tracers that typically bind to cell surface biomarkers, ¹⁸FF-AraG accumulates in activated T-cells due to elevated deoxyguanosine kinase (dGK) activity and reduced SAMHD1 expression, serving as a functional imaging biomarker of immune activation. This review summarizes current preclinical and clinical evidence on ¹⁸FF-AraG PET imaging as a tool for immune monitoring, examining its molecular mechanism, immune cell specificity, and performance in detecting early treatment responses. Compared with anti-CD8-targeted radiotracers, ¹⁸FF-AraG offers distinct advantages by distinguishing active from inert immune cell infiltration. Early clinical data demonstrate that ¹⁸FF-AraG PET images can capture treatment response within days of treatment initiation. Furthermore, the review discusses future directions for clinical integration, including its potential in treatment stratification, adaptive therapy guidance, and combination with other imaging modalities. These complementary PET strategies enable non-invasive functional immune monitoring by assessing T cell activation, cytotoxic engagement, and spatial infiltration, thereby advancing personalized, immune-guided treatment. Realizing this potential requires prospective clinical validation, harmonized quantitative standards, and continued development of short-lived radionuclide-labeled constructs optimized for spatial resolution, patient scheduling, and radiation burden.
Almutairi et al. (Sun,) studied this question.