OTUD1 downregulates PD-L1 expression by deubiquitinating STAT3 and promotes the immune response in CcRCC.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the urinary system and has the highest mortality rate. In addition to surgical tumor reduction, systemic drug therapy is the most important treatment method for metastatic renal cancer. In recent years, immunotherapeutic drugs represented by PD-1 antibodies have been used in the treatment of metastatic ccRCC and achieved good therapeutic effects. However, due to the occurrence of immune escape, only about 50-60% of patients with advanced renal cancer can significantly benefit from immunotherapy. The mechanism of immune escape is extremely complex and has not been clarified. We intend to delve into the driving mechanisms of immune evasion in ccRCC and explore potential targets for intervention.

Methods: In this study, we analyzed the expression of OTUD1 and related pathways in ccRCC through TCGA, GEO dataset, and cBioPortal web tool. At the same time, a mouse model of allogeneic transplanted clear cell renal cell carcinoma was constructed, and the effect of OTUD1 on anti-PD1 antibody therapy was discussed. Experiments such as co-IP, flow cytometry, and RNA-seq analysis were used to investigate the mechanism by which OTUD1 regulates immunity through STAT3.

Results: This study reveals that OTUD1 suppresses PD-L1 expression and enhances antitumor immunity in clear cell renal cell carcinoma (ccRCC) by deubiquitinating and stabilizing STAT3, thereby inhibiting its nuclear translocation and transcriptional activity. As a key regulator of the JAK-STAT pathway, OTUD1 disrupts PD-1/PD-L1-mediated immune evasion, offering a potential therapeutic strategy to improve immunotherapy responses in ccRCC. These findings highlight the OTUD1-STAT3-PD-L1 axis as a novel mechanism for overcoming immune checkpoint resistance.

Conclusion: Overall, we demonstrate that OTUD1 interacts with STAT3 and deubiquitinates, inhibits its nuclear translocation and activity, and ultimately inhibits immune evasion of ccRCC by downregulating PD-L1.