Programmed death ligand-1(PD-L1)/PD-1 checkpoint extensively serves as a central mediator of immunosuppression.A tumor-promoting role for abundant PD-L1 in several cancers is revealed.However,the importance of PD-L1 and how the PD-L1 expression is controlled in breast cancer remains obscure.Here,the mechanisms of controlling PD-L1 at the transcription and protein acetylation levels in promoting breast cancer growth are presented.Overexpressed PD-L1 accelerates breast cancer growth in vitro and in vivo.RNA-seq uncovers that PD-L1 can induce some target genes affecting many cellular processes,especially cancer development.In clinical breast cancer tissues and cells,PD-L1 and HBXIP are both increased,and their expressions are positively correlated.Mechanistic exploration identifies that HBXIP stimulates the transcription of PD-L1 through co-activating ETS2.Specifically,HBXIP induces PD-L1 acetylation at K270 site through interacting with acetyltransferase p300,leading to the stability of PD-L1 protein.Functionally,depletion of HBXIP attenuates PD-L1-accelerated breast tumor growth.Aspirin alleviates breast cancer via targeting PD-L1 and HBXIP.Collectively,the findings display new light into the mechanisms of controlling tumor PD-L1 and broaden the utility for PD-L1 as a target in breast cancer therapy.