The diagnosis and surveillance of clear cell renal cell carcinoma (ccRCC) remains a clinical challenge. The high and specific expression of the cluster of differentiation 70 (CD70) in ccRCC makes it a potential diagnostic and therapeutic target. Methods: We detected and analyzed CD70 expression in various renal cell carcinomas (RCCs) and normal kidneys using immunohistochemical staining. Two novel CD70-specific single-domain antibodies, RCCB3 and RCCB6, were produced and labeled with ⁶⁸Ga to develop radiotracers. We performed immuno-PET/CT imaging with [⁶⁸Ga]Ga-NOTA-RCCB3 and [⁶⁸Ga]Ga-NOTA-RCCB6 in subcutaneous ccRCC patient-derived xenograft models. We recruited 8 RCC patients in a pilot clinical trial (ClinicalTrials.gov identifier: NCT06148220) to evaluate the diagnostic utility of [⁶⁸Ga]Ga-NOTA-RCCB3 and [⁶⁸Ga]Ga-NOTA-RCCB6 immuno-PET/CT. Results: Expression of CD70 is associated with sex, tumor differentiation, tumor thrombus, necrosis, distant metastasis, and overall survival of RCC patients. RCCB3 and RCCB6 had high affinities for recombinant human CD70. Immuno-PET/CT imaging with [⁶⁸Ga]Ga-NOTA-RCCB3 and [⁶⁸Ga]Ga-NOTA-RCCB6 rapidly visualized subcutaneous ccRCC with clarity. Tumor uptake of [⁶⁸Ga]Ga-NOTA-RCCB6 was significantly reduced after the blockade of CD70. [⁶⁸Ga]Ga-NOTA-RCCB6 PET/CT in ccRCC patients outperformed traditional ¹⁸F-FDG PET/CT in specifically identifying CD70-positive ccRCC metastases. Conclusion: CD70-targeted immuno-PET/CT imaging with [⁶⁸Ga]Ga-NOTA-RCCB6 or [⁶⁸Ga]Ga-NOTA-RCCB3 is a precise and superior method for evaluating tumor burden and suspected metastases in ccRCC patients. This advancement in imaging technology has the potential to improve the clinical decision-making process for this patient cohort significantly.

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