Recent Advances in Cyclic Peptide-Based Therapeutic Strategies for Renal Cell Carcinoma: A Focused Review

Abstract

Abstract Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), remains difficult to control after resistance to targeted therapy or immune checkpoint blockade develops. Cyclic peptides provide conformationally constrained and chemically adaptable scaffolds for direct target modulation, tumor-selective payload delivery, radiotheranostics, supramolecular assembly, and induced-proximity pharmacology. This focused mini-review groups cyclic peptide-based strategies according to the role played by the peptide in the therapeutic system. The peptide may act as the drug itself, carry a drug or radionuclide, guide a larger carrier, assemble into a drug-delivery material, or bring two proteins together. Direct RCC evidence is anchored by carbonic anhydrase IX (CAIX)-targeted DPI-4452/ZH2 radiotheranostics, cyclic Arg-Gly-Asp (cRGD)-guided small interfering RNA (siRNA) delivery to tumor endothelium, and PB1-p62-mediated polybromo 1 (PBRM1) degradation and immune sensitization. Drug-resistant non-RCC models are retained only as transferable design evidence for efflux-evasive or self-assembling delivery. We further discuss target heterogeneity, linker and assembly stability, pharmacokinetics, renal distribution, scalable synthesis, and the experimental controls required to attribute benefit to the cyclic peptide component. Although clinical therapeutic evidence remains limited, the emerging RCC-specific studies support a mechanism-matched development strategy for this drug class.