Visualizing T-cell activation: PET imaging of CXCL9 as a window into the tumor immune response

T-cell activation within the tumor microenvironment is a key determinant of response to immunotherapy, yet current biomarkers fail to capture its spatial and temporal dynamics. Traditional assays such as PD-L1 immunohistochemistry, tumor mutational analysis, and circulating cytokine profiling offer static or systemic snapshots that inadequately reflect localized immune engagement. Positron emission tomography (PET) provides a unique opportunity to visualize these processes <i>in vivo</i>. Among emerging tracers, CXCL9-targeted imaging stands out as a promising approach to quantify IFNγ-driven T-cell activation and recruitment. Jacobson <i>et al</i>. report the development of [¹⁸F]F-h2A12, a high-affinity nanobody PET tracer specific for CXCL9. Preclinical studies demonstrate robust uptake in CXCL9-expressing tumors, close correlation with intratumoral immune activation, and clear distinction from blood-based biomarkers. Compared with existing immune PET tracers that target cytotoxic enzymes, soluble cytokines, or surface activation markers, CXCL9 imaging offers an advantageous balance of specificity, localization, and functional relevance. By visualizing the chemokine gradients that govern T-cell trafficking, CXCL9 PET could serve as an early, noninvasive biomarker of immunotherapy response and a powerful tool for guiding adaptive treatment strategies.