Beyond Expression: Molecular Imaging of Claudin18.2 to Decipher Target Accessibility and Guide Precision Oncology

Claudin18.2 (CLDN18.2) has emerged as a clinically important therapeutic target in gastrointestinal malignancies following the success of zolbetuximab-based therapy. However, unlike conventional overexpression-driven biomarkers, the clinical relevance of CLDN18.2 is fundamentally shaped by target accessibility rather than expression alone. Physiologically concealed within gastric epithelial tight junctions, CLDN18.2 becomes exposed during malignant transformation, creating a spatially heterogeneous and dynamically accessible target landscape. This exposure-dependent biology challenges conventional tissue-based assessment and provides a strong rationale for molecular imaging. Recent advances in CLDN18.2-targeted molecular imaging across antibody, engineered-fragment, and nanobody platforms have enabled noninvasive whole-body assessment of target accessibility and lesion-level heterogeneity beyond localized biopsy. Importantly, imaging signals reflect not only antigen expression, but also probe-dependent pharmacokinetics, tissue penetration, and microenvironmental accessibility. In this review, we discuss the biological basis of CLDN18.2 accessibility, summarize emerging imaging and theranostic strategies, and examine the evolving role of molecular imaging in patient stratification and imaging-informed precision oncology.