摘要
Multiple myeloma(MM)is regarded as a hematological malignancy and it is challenging to cure,largely caused by the increased risk of relapse or the emergence of resistance to the existing therapies.In MM immunotherapy,the utilization of programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking therapy has been a significant cornerstone.However,currently,there is an urgent demand for small-molecule checkpoint inhibitors with advantageous pharmacokinetic properties compared to antibodies that are currently being tar-geted.In this study,Momordin Ic was detected to be a negative regulator of PD-L1.Momordin Ic improved the sensitivity of MM cells to co-cultured T-cells through reducing the level of PD-L1 in MM cells.Momordin Ic made its antitumor impact on 8226 tumor xenograft mice and patient-derived xenografts(PDX)model by improving tumor infiltrating T-cell immunity and reducing the activation of immunosuppressive myeloid-derived sup-pressor cells(MDSCs)and regulatory T-cells(Tregs).Momordin Ic induced PD-L1 degradation via ubiquitin(Ub)/proteasome-dependent pathway.Momordin Ic facilitates the recruitment of E3 ligase SYVN1,contributing to the ubiquitination and subsequent degradation of PD-L1.Moreover,the current work is the first to demon-strate that Momordin Ic possesses therapeutic potential for treating MM by targeting the degradation of PD-L1 through the recruitment of SYVN1.
基金
the support of Science and Technology Planning Project of Guangdong Province(No.2023B1212060063).
