Background <p>Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a very rare and aggressiveness malignancy with poor outcome. Previous studies suggested that programmed cell death protein-1 ligand 1 (PDL1) was characterized with high mRNA and low protein in Xp11.2 tRCC, however, the potential mechanism is still blurry.</p> Methods <p>Immunohistochemistry was conducted to verify Cyclin D1 and PDL1 expression in Xp11.2 tRCC. ChIP and dual-luciferase reporter gene assay were applied to evaluate transcriptional-regulation of TFE3 fusion proteins on <i>CCND1</i>/Cyclin D1 and NR1D1, we used RNA-seq to detect the regulation role of NR1D1 on <i>CCND1</i>/Cyclin D1, half-life experiment and autophagy flux were employed to demonstrate Cyclin D1-CDK4 speeded PDL1 degradation.</p> Results <p>Here, we demonstrated that <i>CCND1</i>/Cyclin D1 was not only a direct target gene for positive regulation of TFE3 fusion proteins, but also up-regulated by nuclear receptor subfamily 1 group D member 1 (NR1D1) which was positively transcriptional regulation of TFE3 fusion proteins. Besides, TFE3 fusion proteins reduced the degradation of Cyclin D1 by activating the AKT/mTOR pathway. As a result, the high-expression of <i>CCND1</i>/Cyclin D1 mediated degradation of PDL1 protein through ubiquitin-proteasome system and autophagy pathway.</p> Conclusion <p>This research found that <i>CCND1</i>/Cyclin D1 was upregulated in Xp11.2 tRCC through three mechanisms, high-expression <i>CCND1</i>/Cyclin D1 inducing PDL1 degradation. Overall, the study provided a theoretical basis for sequentially using CDK4 inhibitors and anti-PDL1 for Xp11.2 tRCC treatment.</p> Clinical trial number <p>Not applicable.</p>