PSMA PET in renal cell carcinoma: an update and future aspects

Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has recently emerged as a promising molecular imaging tool for renal cell carcinoma (RCC), particularly for the clear-cell subtype (ccRCC). Unlike its expression in prostate cancer, PSMA in ccRCC is localised mainly to the endothelial cells of tumour-associated neovasculature, where it reflects angiogenic activity driven by the VHL-HIF-VEGF axis. This biological substrate provides the rationale for using PSMA-targeted imaging as a surrogate of angiogenesis and as a potential predictive biomarker in systemic therapy. Evidence from retrospective and prospective studies demonstrates high diagnostic accuracy of PSMA PET/CT in ccRCC, with detection rates exceeding 80-90%, outperforming conventional imaging and [¹⁸F]FDG PET/CT, particularly in metastatic disease. Quantitative PET-derived parameters, including SUVmax and heterogeneity indices, have shown correlation with VEGFR-2, PDGFR-β, and HIF-2α expression and may serve as predictors of response to tyrosine kinase inhibitors and immunotherapy combinations. PSMA-guided metastasis-directed therapy has also shown encouraging control rates in oligometastatic settings. Beyond its diagnostic role, PSMA PET offers a foundation for theragnostic applications. Early clinical experience with [¹⁷⁷Lu]Lu-PSMA radioligands and ongoing trials such as RENALUT and PRadR are exploring the feasibility of radioligand therapy targeting PSMA-positive ccRCC neovasculature. Although biological and kinetic barriers persist, PSMA-based imaging and therapy represent a feasible, rapidly translatable platform that bridges diagnosis and targeted treatment, marking a pivotal step towards personalised, imaging-guided management of advanced ccRCC.