PTPRZ1 dephosphorylates and stabilizes RNF26 to reduce the efficacy of TKIs and PD-1 blockade in ccRCC.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often exhibits resistance to tyrosine kinase inhibitors (TKIs) when used as monotherapy. However, the integration of PD-1 blockade with TKIs has significantly improved patient survival, making it a leading therapeutic strategy for ccRCC. Despite these advancements, the efficacy of this combined therapy remains suboptimal, necessitating a deeper understanding of the underlying regulatory mechanisms. Through comprehensive analyses, including mass spectrometry, RNA sequencing, lipidomic profiling, immunohistochemical staining, and ex vivo experiments, we explored the interaction between PTPRZ1 and RNF26 and its impact on ccRCC cell behavior. Our results revealed a unique interaction where PTPRZ1 stabilized RNF26 protein expression by dephosphorylating it at the Y432 site. The modulation of RNF26 levels by PTPRZ1 was found to be mediated through the proteasome pathway. Additionally, PTPRZ1, via its interaction with RNF26, activated the TNF/NF-κB signaling pathway, thereby promoting cell proliferation, angiogenesis, and lipid metabolism in ccRCC cells. Importantly, inhibiting PTPRZ1 enhanced the sensitivity of ccRCC to TKIs and PD-1 blockade, an effect that was attenuated when RNF26 was simultaneously knocked down. These findings highlight the critical role of the PTPRZ1-RNF26 axis in ccRCC and suggest that combining PTPRZ1 inhibitors with current TKIs and PD-1 blockade therapies could significantly improve treatment outcomes for ccRCC patients.