biostudies-literatureXiong WNational Natural Science Foundation of ChinaNCI NIH HHS1700https://www.ebi.ac.uk/biostudies/studies/S-EPMC8971425biostudies-literatureUnknown13(1)Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. BasNature communicationsUSP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.PMC8971425P50 CA101942R37 CA25116531970732Li HHe CZhang JZhang HXiao XChen GWei WShu HBWang HSun YXiong WXiao BLXiang BFreeman GJZhang TBu XZhang LZGao YJiang BGao XShi JXie CHu MMfalseUSP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Bas2022-01-01T00:00:00Z2022 Mar2026-07-14T14:42:31.155Z2025-04-07T09:41:17.167ZS-EPMC89714253536179910.1038/s41467-022-29401-6