The dual role of retinoic acid signaling in clear cell renal cell carcinoma and wilms tumor: A tale of two entities.

The retinoic acid (RA) signaling pathway is indispensable for kidney development. However, owing to differences in tumor subtypes, genetic mutation backgrounds, and subcellular localization of key molecules, RA exhibits paradoxical dual functions in clear cell renal cell carcinoma (ccRCC) and Wilms tumor (WT). Depending on the pathological conditions, RA may induce differentiation, inhibit proliferation and metastasis, or promote epithelial-mesenchymal transition (EMT), maintain an undifferentiated state, and accelerate tumor progression, thus presenting considerable challenges. This review systematically analyzes the bidirectional regulatory mechanisms of RA signaling in ccRCC and WT as separate entities. In ccRCC, retinoic acid receptor responder 1 (RARRES1) exerts tumor-suppressive effects by regulating tumor-associated macrophage polarization, whereas loss of polybromo-1 (PBRM1) leads to cytoplasmic RARRES1 localization, shifting its function toward oncogenic promotion. In WT, all-trans retinoic acid (ATRA) can induce tumor cell differentiation, but abnormal retinoic acid receptor (RAR) activation and cytoplasmic retention of cellular retinoic acid-binding protein 2 (CRABP2) maintain an undifferentiated state. Thus, a molecular switch model is proposed in which the net output of RA signaling is dictated by the integration of genetic (VHL/PBRM1/WT1), epigenetic (RARB promoter methylation), and subcellular (RARRES1/CRABP2 localization) determinants, together with nuclear receptor crosstalk, particularly competition between RARs and PPARγ for limiting retinoid X receptor (RXR) pools. Based on these mechanisms, we summarize the current clinical status of RA combination therapy and critically reassess historical trials, acknowledging that interferon-α-based regimens are no longer clinically relevant and that true RA synergy remains unproven. This review proposes that future precision medicine approaches should be stratified according to tumor subtype, genetic mutation background, and RARRES1/CRABP2 localization to overcome treatment resistance. Considering the limitations of current cell line-based data and the underexplored contribution of stromal cells, we recommend a biomarker-driven, mechanism-guided approach to clinical development, incorporating HDAC inhibitors, liposomal formulations, and immune checkpoint inhibitors as rational combination partners.