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.

透明细胞肾细胞癌 （ccRCC） 的诊断和监测仍然是一项临床挑战。ccRCC 中分化簇 70 （CD70） 的高特异性表达使其成为潜在的诊断和治疗靶点。方法：我们使用免疫组织化学染色检测并分析了各种肾细胞癌 （RCC） 和正常肾脏中的 CD70 表达。产生两种新型 CD70 特异性单域抗体 RCCB3 和 RCCB6，并用 ⁶⁸Ga 标记以开发放射性示踪剂。我们在皮下 ccRCC 患者来源的异种移植模型中使用 [⁶⁸Ga]Ga-NOTA-RCCB3 和 [⁶⁸Ga]Ga-NOTA-RCCB6 进行免疫 PET/CT 成像。我们在一项初步临床试验中招募了 8 例 RCC 患者 （ClinicalTrials.gov 标识符：NCT06148220） 来评估 [⁶⁸Ga]Ga-NOTA-RCCB3 和 [⁶⁸Ga]Ga-NOTA-RCCB6 免疫 PET/CT 的诊断效用。结果： CD70 的表达与 RCC 患者的性别、肿瘤分化、癌栓、坏死、远处转移和总生存期相关。RCCB3 和 RCCB6 对重组人 CD70 具有高亲和力。使用 [⁶⁸Ga]Ga-NOTA-RCCB3 和 [⁶⁸Ga]Ga-NOTA-RCCB6 进行免疫 PET/CT 成像可快速清晰地显示皮下 ccRCC。阻断 CD70 后，肿瘤对 [⁶⁸Ga]Ga-NOTA-RCCB6 的摄取显著降低。[⁶⁸加]ccRCC 患者的 Ga-NOTA-RCCB6 PET/CT 在特异性识别 CD70 阳性 ccRCC 转移方面优于传统的 ¹⁸F-FDG PET/CT。结论：使用 [⁶⁸Ga]Ga-NOTA-RCCB6 或 [⁶⁸Ga]Ga-NOTA-RCCB3 进行 CD70 靶向免疫 PET/CT 成像是评估 ccRCC 患者肿瘤负荷和疑似转移的精确且优越的方法。 成像技术的这一进步有可能显着改善该患者群体的临床决策过程。