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DPP9 inhibition boosts antitumor immunity by disrupting BRISC-mediated PD-L1 expression in clear cell renal cell carcinoma

Cell Death & Differentiation (2026)Cite this article

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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.

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Fig. 1: DPP9 overexpression promotes tumor growth and immune evasion, counteracted by the DPP8/9 Inhibitor 1G244.
Fig. 2: DPP9 enhances tumor resistance to T cell-mediated cytotoxicity, counteracted by the DPP8/9 Inhibitor 1G244.
Fig. 3: Targeting DPP9 with 1G244 Downregulates PD-L1 Expression.
Fig. 4: Anti-PD-L1 therapy reverses Dpp9-induced tumor immune evasion.
Fig. 5: DPP9 dissociates SHMT2 from the BRISC Complex.
Fig. 6: DPP9 enhances the IFNAR1-JAK-STAT-IRF1-PD-L1 Pathway via BRISC-Mediated IFNAR1 deubiquitination and stabilization.
Fig. 7: Synergistic antitumor effects of 1G244 and CTLA-4 blockade in enhancing immune activation and tumor suppression.
Fig. 8: Correlation Between DPP9 and PD-L1 Expression in ccRCC.

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Data availability

The original MS proteomics data, which have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (www.ebi.ac.uk/pride) with the dataset [48] identifiers PXD059150 and PXD059151.

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Funding

This work was supported in part by the National Natural Science Foundation of China (No. 81902614 to K.C.; No. 92357301, 32370726, and 81972396 to C.W.; No. 82473192, 82172741 to D.Y.; No. 32500513 to Y.C), the State Key Development Programs of China (No. 2022YFA1104200 to C.W.), the Natural Science Foundation of Shanghai (22ZR1406600 to C.W) and Science and Technology Research Program of Shanghai (No. 9DZ2282100 to C.W).

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  1. These authors contributed equally: Wei Zhang, Yue Wang, Tao Feng.

Authors and Affiliations

  1. Department 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

    Wei Zhang

  2. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Yue Wang, Tao Feng, Tingting Cai, Wenfeng Wang, Shuxuan Zhu, Hailiang Zhang, Dingwei Ye & Kun Chang

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Yue Wang, Tao Feng, Tingting Cai, Wenfeng Wang, Shuxuan Zhu, Hailiang Zhang, Dingwei Ye & Kun Chang

  4. Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China

    Yingji Chen & Chenji Wang

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Contributions

W.Z., Y.W., and K.C. performed most of the experiments and contributed to writing and revising the manuscript. C.W., K.C., and D.Y. conceived the study, participated in its design and coordination and helped draft the manuscript. T.C., H.Z., Y.C., and S.Z. collected clinical samples. T.F. and W.W. analyzed part of the data. All the authors have read and approved the final manuscript.

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Correspondence to Dingwei Ye, Chenji Wang or Kun Chang.

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Ethics

All animal experiments were approved by the Ethics Review Committee for Animal Experimentation of Fudan University Shanghai Cancer Center (No: IACUC-S2024-0273). Human tissue samples were obtained with written informed consent, and the study was approved by the Ethics Review Committee of Fudan University Shanghai Cancer Center (No: 050432-4-2108*).

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Zhang, W., Wang, Y., Feng, T. et al. DPP9 inhibition boosts antitumor immunity by disrupting BRISC-mediated PD-L1 expression in clear cell renal cell carcinoma. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01704-x

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