{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Xiong W"],"funding":["National Natural Science Foundation of China","NCI NIH HHS"],"pagination":["1700"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8971425"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(1)"],"pubmed_abstract":["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. Bas"],"journal":["Nature communications"],"pubmed_title":["USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy."],"pmcid":["PMC8971425"],"funding_grant_id":["P50 CA101942","R37 CA251165","31970732"],"pubmed_authors":["Li H","He C","Zhang J","Zhang H","Xiao X","Chen G","Wei W","Shu HB","Wang H","Sun Y","Xiong W","Xiao BL","Xiang B","Freeman GJ","Zhang T","Bu X","Zhang LZ","Gao Y","Jiang B","Gao X","Shi J","Xie C","Hu MM"],"additional_accession":[]},"is_claimable":false,"name":"USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.","description":"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. Bas","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2026-07-14T14:42:31.155Z","creation":"2025-04-07T09:41:17.167Z"},"accession":"S-EPMC8971425","cross_references":{"pubmed":["35361799"],"doi":["10.1038/s41467-022-29401-6"]}}