Malignant tumors represent one of the major diseases threatening human health, with their incidence and mortality rates continuing to rise and showing a trend toward younger age groups, presenting a severe challenge for prevention and treatment. Renal cell carcinoma (RCC) is the most common pathological type among kidney malignancies, accounting for approximately 70% of all kidney cancers. As a highly invasive tumor, approximately 30% of RCC patients present with distant metastases at initial diagnosis, and the postoperative recurrence or metastasis rate also reaches 30%. Therefore, early precise diagnosis and accurate tumor burden assessment are crucial for improving patient prognosis, and rational clinical staging forms the foundation for developing individualized treatment strategies.
Currently, imaging diagnosis and postoperative monitoring of renal cell carcinoma primarily rely on contrast-enhanced computed tomography (CT), but this method has limitations, particularly the lack of efficient and reliable whole-body assessment tools. Due to the generally low uptake of 18F-fluorodeoxyglucose (\[18F\]FDG) in RCC, the application value of conventional \[18F\]FDG positron emission tomography/computed tomography (PET/CT) in RCC diagnosis and monitoring is limited. Furthermore, \[18F\]FDG PET/CT lacks sufficient specificity in distinguishing benign from malignant renal masses, as some benign lesions may also exhibit increased FDG uptake. Consequently, developing highly sensitive and specific molecular imaging methods to optimize RCC diagnosis and staging has become an urgent clinical priority.
Nuclear medicine testing targeting RCC-specific markers holds promise for addressing this challenge. In recent years, prostate-specific membrane antigen (PSMA) PET/CT imaging has demonstrated significant value in prostate cancer staging. Multiple studies indicate PSMA overexpression in endothelial cells of neovascularization across various tumors. Although preliminary data suggest PSMA PET/CT may aid in predicting RCC histological grading and adverse prognosis, its precise role in RCC clinical management remains unclear. Furthermore, based on multi-omics analysis and large-scale pathological studies, carbonic anhydrase IX (CAIX) and CD70 have been identified as two prominent potential specific targets in RCC.
CAIX, a transmembrane metalloproteinase involved in regulating tumor microenvironment pH, exhibits a significant positive correlation between its expression levels and tumor hypoxia, making it an important marker for poor prognosis. Notably, due to VHL gene inactivation mutations and subsequent sustained activation of the downstream HIF-1α signaling pathway, CAIX expression is upregulated in over 95% of RCC cases. Beyond the gastrointestinal and biliary tract systems, CAIX is scarcely detectable in normal tissues, making it an ideal target for molecular imaging and targeted therapy in RCC.
CD70 (CD27 ligand), belonging to the tumor necrosis factor superfamily (TNFSF7), is normally expressed transiently on activated T cells, B cells, NK cells, and mature dendritic cells under physiological conditions. Recent studies indicate that CD70 is abnormally overexpressed in 78% of clear cell RCC and 32% of papillary RCC, while absent in normal renal tissue. Furthermore, dysregulation of the CD70-CD27 axis in tumor cells and the microenvironment contributes to immune evasion and tumor progression. CD70 expression on tumor cells is also strongly associated with poor prognosis in multiple malignancies. Currently, eliminating CD70-positive tumor cells or blocking the CD70-CD27 signaling axis represents a novel therapeutic direction for renal cell carcinoma. Monoclonal antibodies and antibody-drug conjugates targeting CD70 have entered clinical trial phases. Therefore, developing a radiolabeled tracer targeting CD70 holds significant clinical and practical value. It not only facilitates precise diagnosis and staging of RCC but also provides crucial evidence for studying CD70-related immunotherapy mechanisms.
In summary, this project aims to explore the clinical application value of PET imaging technologies targeting PSMA, CAIX, and CD70 in renal cell carcinoma. By utilizing PSMA-targeted PET radiopharmaceuticals (e.g., \[68Ga\]Ga-PSMA), CAIX-targeted PET tracers (e.g., \[68Ga\]Ga-DOTA-CAIX peptide), and CD70-targeted PET tracers (e.g., \[68Ga\]Ga-NOTA-CD70 antibody fragment) in clinically suspected or confirmed renal cell carcinoma patients and healthy volunteers. Integrated PET/MR or PET/CT imaging will be performed to facilitate diagnosis and staging of renal cell carcinoma, assess tumor burden, and evaluate PSMA and CD70 expression, assisting in determining treatment strategies. Concurrently, preliminary pharmacokinetic analysis of the novel CAIX-targeting molecular probe will be conducted in healthy volunteers to elucidate its metabolic patterns and adverse reactions in vivo.
