ABSTRACT: Background: ccRCC, the most prevalent pathological subtype of renal cell carcinoma, has demonstrated a proclivity for drug resistance when treated with TKIs as a monotherapy. Notably, the integration of PD-1 blockade with TKIs has significantly enhanced patient survival, thereby emerging as a frontline therapeutic approach for ccRCC. However, the efficacy of this combined therapy still holds room for improvement. Consequently, there is a pressing need to delve deeper into the regulatory mechanisms that govern the effectiveness of TKIs/PD-1 blockade combination therapy in ccRCC. Methods: By mass spectrometry, RNA sequencing, lipidomic analysis, immunohistochemical staining and ex vivo experiments, we investigated the interaction between PTPRZ1 and RNF26 and their effects on the biological behavior of ccRCC cells. Results: Our findings revealed a distinct interaction between PTPRZ1 and RNF26 in ccRCC cells, wherein PTPRZ1 stabilized RNF26's protein expression by dephosphorylating it at the Y432 site. Notably, the overexpression or knockdown of PTPRZ1 significantly modulated the protein level of RNF26, and this phenomenon was linked to the proteasome pathway. Furthermore, PTPRZ1, through its interaction with RNF26, activated the TNF/NF-κB signaling pathway, ultimately promoting proliferation, angiogenesis, and regulating lipid metabolism in ccRCC cells. Crucially, inhibiting PTPRZ1 enhanced the sensitivity of ccRCC to TKIs and PD-1 blockade, an effect that was mitigated when RNF26 was co-knocked down. Conclusion: Our study underscores the significant role of the PTPRZ1-RNF26 axis in ccRCC, indicating that a combined approach utilizing PTPRZ1 inhibitors alongside existing TKIs and PD-1 blockade therapies could potentially enhance the therapeutic outcomes for ccRCC patients.
