CA9‐Targeted PET Imaging for Noninvasive Discrimination of Clear Cell Renal Cell Carcinoma and Associated Tumor Biological Features

ABSTRACT Purpose Clear cell renal cell carcinoma (ccRCC) is biologically distinct from non‐clear cell renal cell carcinoma (nccRCC), and shows marked intratumoral heterogeneity, yet current imaging modalities lack the ability to noninvasively distinguish histologic subtypes or capture tumor biological features in vivo. Experimental Design An integrative analysis combines CA9‐targeted positron emission tomography (PET) imaging with multi‐omic analyses, histopathological validation, and functional assessment using patient‐derived xenograft (PDX) models. Clinical CA9‐targeted PET imaging is evaluated in patients with renal masses and examined alongside ¹⁸ F‐FDG PET. Results CA9 is preferentially enriched in ccRCC tumor cells with low background expression in normal kidney tissue. CA9‐targeted PET imaging shows potential for noninvasive discrimination of ccRCC from nccRCC, including lesions with distinct histologies within individual patients. High CA9‐targeted PET uptake is associated with PBRM1 loss‐of‐function alterations, immune pathway suppression with reduced B cell infiltration, metabolic alterations, and enhanced angiogenic activity. Single‐cell and spatial analyses support endothelial enrichment and angiogenesis‐associated programs in CA9‐high regions. CA9‐high PDX models showed greater tumor growth inhibition under axitinib treatment. Conclusions CA9‐targeted PET provides proof‐of‐concept evidence for noninvasive discrimination of ccRCC and associated angiogenic and tumor biological features, warranting prospective validation.