Promises and Challenges of Metabolic Imaging: Where Does 18F-FDG Stand in the Immunometabolism Era? (perspective on “Intratumoral Distribution of Fluorine-18-Fluorodeoxyglucose In Vivo: High Accumulation in Macrophages and Granulation Tissues Studied by Microautoradiography” J Nucl Med. 1992;33:1972–1980)
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* Sina Tavakoli

Since its development in the late 1970s, 18F-FDG has been a major driver of basic science and translational discoveries, which have revolutionized the day-to-day clinical practice of nuclear imaging (1). Initially launched as a tracer for imaging brain metabolism, 18F-FDG rapidly found its major applications in oncologic imaging through detection of cancer-associated enhanced glucose utilization and aerobic glycolysis, referred to as the Warburg effect (1). 18F-FDG PET is now an inseparable imaging modality for the diagnosis, staging, and monitoring of therapeutic response for a variety of cancers. Beyond oncology, 18F-FDG PET has been widely used in a multitude of infectious and inflammatory diseases, including sarcoidosis and vasculitis (2). Despite this widespread clinical use, the biologic basis of 18F-FDG uptake in inflammation has been an evolving concept for nearly 3 decades.

The paper by Kubota et al. in this anniversary issue of *JNM* was a landmark study highlighting the significance of 18F-FDG uptake by tumor macrophages in a mouse xenograft model during the initial years of 18F-FDG biologic validation (3). This study extended the existing knowledge about the accumulation of 18F-FDG in abscesses and other inflamed tissues by elegantly demonstrating that immune cells, and notably macrophages, are a major contributor of 18F-FDG uptake in tumors (3). Through a series of meticulous dual-isotope (14C and 18F) high-resolution autoradiography images, the authors demonstrated that macrophages surrounding the necrotic part of tumors and the inflammatory granulation tissue in the periphery of tumors have a markedly higher uptake of 18F-FDG than do malignant tumor cells (3).

After nearly 3 decades, it is now well recognized that tumor-associated macrophages may constitute a large fraction of tumor mass and are critical players throughout different stages of tumorigenesis, from cancer initiation to local spread and metastasis (4). Moreover, growing immunometabolic discoveries have highlighted the cross talk between cell metabolism and macrophage biology, which may be exploited as novel targets for cancer diagnosis, risk stratification, and therapy (4). However, the field of immunometabolism has been driven largely through ex vivo techniques, such as stable isotope metabolic tracing, which do not accurately reflect the complexities of the natural microenvironment of tumor or inflammatory tissues.

Metabolic imaging is well positioned to address the dire need to define metabolism in vivo. However, major challenges are yet to be overcome, particularly for metabolic assessment of complex and heterogeneous tissues, such as tumors. The spatial resolution of PET does not allow 18F-FDG uptake by malignant cells to be distinguished from uptake by tumor-associated macrophages or other tumor constituents. Therefore, unraveling the biologic significance of 18F-FDG uptake by tumor-associated macrophages and its implications for prognostication of patients (e.g., determining tumor aggressiveness) and monitoring the response to therapy remain an ongoing challenge. Complementing in vivo PET studies by high-resolution microautoradiography (as in Kubota et al. (3)) or state-of-the-art metabolomics techniques (e.g., mass spectrometry imaging (5)) advances our knowledge about the heterogeneity of immune cell metabolism within the tumor microenvironment. The limited specificity of 18F-FDG, which targets a nearly ubiquitous metabolic process, is another major challenge for the elucidation of immunometabolic links between tumor-associated macrophages and tumor biology by in vivo imaging.

A multipronged approach that includes developing novel tracers with more specific metabolic targets, imaging additional pathways other than glucose uptake, and improving the spatial resolution of PET (e.g., by total-body acquisition), along with careful histologic validations, will be vital to reinforce the role of in vivo imaging in understanding immunometabolism.

## DISCLOSURE

The author is supported by the National Institutes of Health (NHLBI K08-HL144911). No other potential conflict of interest relevant to this article was reported.

*   © 2020 by the Society of Nuclear Medicine and Molecular Imaging.

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*   Received for publication June 16, 2020.
*   Accepted for publication June 18, 2020.