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Updated: Mar 15, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
DPP9 inhibition boosts antitumor immunity by disrupting BRISC-mediated PD-L1 expression in clear cell renal cell
Wei Zhang1, Yue Wang2,3, Tao Feng2,3
1Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Abstract:
Programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1) are key mediators of immune checkpoint blockade therapy in clear cell renal cell carcinoma (RCC). However, immune evasion and primary resistance often limit their efficacy, highlighting the need for improved strategies. Here, we identified dipeptidyl peptidase 9 (DPP9) as a critical regulator of PD-L1 expression in ccRCC. Pharmacological inhibition of DPP9 with 1G244 restores T cell cytotoxicity and enhances checkpoint blockade efficacy. Mechanistically, DPP9 disrupts the BRISC-SHMT2 complex, enhancing BRISC-mediated deubiquitination and stabilization of IFNAR1, which activates the JAK/STAT pathway and drives PD-L1 transcription. 1G244 reverses this process by reducing DPP9 interacting with SHMT2, promoting IFNAR1 ubiquitination and degradation, thereby reducing PD-L1 levels and restoring T cell-mediated cytotoxicity. Moreover, the combination of 1G244 and anti-CTLA-4 therapy further enhanced antitumor immunity, highlighting a potential synergistic therapeutic strategy. Collectively, our findings define a novel DPP9-BRISC-SHMT2 regulatory axis in PD-L1 transcriptional control and identify 1G244 as an alternative combinatorial strategy to enhance the efficacy of cancer immunotherapy.
Insights
Researchers discovered dipeptidyl peptidase 9 (DPP9) regulates PD-L1 in clear cell renal cell carcinoma (ccRCC). Inhibiting DPP9 with 1G244 restores anti-tumor immunity and enhances immunotherapy for ccRCC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade therapy targeting PD-1/PD-L1 is crucial for clear cell renal cell carcinoma (ccRCC) treatment.
- Primary resistance and immune evasion limit the efficacy of current immunotherapies for ccRCC.
Purpose of the Study:
- To identify novel regulators of PD-L1 expression in ccRCC.
- To explore DPP9 inhibition as a therapeutic strategy to enhance ccRCC immunotherapy.
Main Methods:
- Investigated the role of dipeptidyl peptidase 9 (DPP9) in ccRCC PD-L1 regulation.
- Utilized pharmacological inhibition of DPP9 with compound 1G244.
- Elucidated the molecular mechanism involving the BRISC-SHMT2 complex and IFNAR1.
- Assessed T cell cytotoxicity and antitumor immunity in combination therapy models.
Main Results:
- DPP9 was identified as a critical regulator of PD-L1 expression in ccRCC.
- Inhibition of DPP9 by 1G244 restored T cell cytotoxicity and improved checkpoint blockade efficacy.
- DPP9 inhibition reversed PD-L1 upregulation by disrupting the DPP9-SHMT2 interaction and promoting IFNAR1 degradation.
- Combination therapy with 1G244 and anti-CTLA-4 demonstrated enhanced antitumor immunity.
Conclusions:
- A novel DPP9-BRISC-SHMT2 regulatory axis controlling PD-L1 transcription was defined.
- 1G244 represents a potential therapeutic agent to enhance cancer immunotherapy efficacy in ccRCC.
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