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

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.