Visualizing the metabolic battleground: the role of PET imaging in understanding immunometabolism and the tumor microenvironment

PET has evolved beyond tumor glucose metabolism imaging to assess the immunometabolic landscape of the tumor microenvironment (TME) and systemic immune responses. Immunometabolism, encompassing glycolysis, oxidative phosphorylation, and fatty acid oxidation, governs immune cell activation, differentiation, and effector function, shaping antitumor immunity and immunotherapy outcomes. PET radiotracers, including fluorine 18-fluorodeoxyglucose, amino acid/nucleoside tracers (11C-methionine, 18F-F-AraG), cytokine/receptor-targeted tracers (64Cu-IFNγ, 68Ga-NOTA-Nb109), and macrophage-directed tracers (11C-PK11195, gallium-68-labeled NOTA-mannosylated serum albumin), enable noninvasive visualization of immune metabolism, proliferation, and polarization. Novel agents such as gallium-68-labeled fibroblast activation protein inhibitor and 68Ga-Pentixafor further capture stromal remodeling and immune cell recruitment. Clinically, immunometabolic PET guides oncology, immunotherapy, autoimmune, inflammatory, and infectious disease management by distinguishing immune activation from tumor progression, evaluating therapeutic response, and identifying active inflammation. This emerging imaging paradigm provides mechanistic insights into immune-tumor interactions and offers a precision tool for personalized treatment strategies.