Isobavachalcone targets deubiquitinase OTUB1 to induce PD-L1 degradation and enhances antitumor immunity

PD-L1-mediated immunosuppression is a key mechanism underlying tumor immune evasion, whereas PD-1/PD-L1 blockade therapies remain limited by low response rates and acquired resistance. Through small-molecule screening, we identify isobavachalcone (IBC), a naturally derived compound that modulates PD-L1 homeostasis by targeting the deubiquitinase OTUB1. Mechanistically, IBC targets OTUB1 at the His217 residue and suppresses its deubiquitinase activity, thereby promoting K48-linked polyubiquitination of PD-L1 and its proteasome-dependent degradation. Functionally, IBC reduces tumor cell PD-L1 expression and enhances CD8 + T cell-mediated cytotoxicity. In PD-L1-deficient tumor models, IBC fails to further enhance antitumor activity, indicating that PD-L1 is required for IBC-mediated immune regulation. Moreover, IBC combined with anti-CTLA-4 therapy further enhanced antitumor efficacy. Together, these findings highlight IBC as a potential drug candidate that promotes PD-L1 degradation and demonstrate the therapeutic potential of targeting the OTUB1-PD-L1 axis to improve immune checkpoint therapy.