Discovery of tumor antigens in renal cell carcinoma and prospects for clinical application.

Renal cell carcinoma (RCC) is a prevalent and heterogeneous malignancy with clear cell RCC (ccRCC) as the most common subtype. Despite advances in surgical, targeted, and immunotherapeutic approaches, prognosis for advanced and metastatic RCC remains poor, and the effectiveness of current immunotherapies is limited by immune tolerance, tumor heterogeneity, and adverse effects. The identification of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) is crucial for the development of personalized and effective antigen-directed therapies, including vaccines, antibodies and adoptive cell therapies. This review summarizes epidemiological data, molecular features of RCC, and the role of the von Hippel Lindau - Hypoxia Inducible Factor (VHL-HIF) signaling pathway in pathogenesis, alongside recent progress in characterizing possible antigen targets for vaccination such as TOP2A, NCF4, FMNL1, DOK3, MUC1, CAIX, CD70, and 5T4. Preclinical models, including genetically engineered mouse models, zebrafish, and various patient-derived xenograft (PDX) systems, are discussed as tools for studying tumor biology and testing immunotherapeutic strategies. Clinical trial data on RCC vaccines, including autologous renal tumor cell vaccination, peptide-based, dendritic cell-based, and viral vector platforms, demonstrate immunogenicity but have not yet yielded clear survival benefits in phase III trials. Future directions emphasize integrating antigen discovery with immune profiling, refining preclinical modeling, and developing personalized vaccines to enhance therapeutic efficacy, particularly for immunologically favorable patient subtypes and for certain applications such as reducing metastasis after surgery. In particular, we discuss carrier-based vaccine approaches for overcoming tolerance and increasing the immunogenicity of vaccines.