Integrins plays critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription, which upregulation is involved in cancer stemness and metastasis. However, the molecular mechanisms underlying how integrins are upregulated in cancer stem cells (CSCs) remain as a biomedical mystery. Herein, we show that the death from cancer signature gene USP22 is essential to maintain the stemness of breast cancer cells through promoting the transcription of a group of integrin family members in particular integrin β1(ITGB1).Both genetic and pharmacological USP22 inhibition largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Integrin β1 reconstitution partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoralITGB1gene transcription. Importantly unbiased analysis of the TCGA database revealed a strong positive correlation between the death from cancer signature gene ubiquitin-specific peptidase 22 (USP22) andITGB1,both of which are critical for cancer stemness, in more than 90% of human cancer types, implying that USP22 functions as a key factor to maintain stemness for a broad spectrum of human cancer types possibly through regulatingITGB1.To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis critical for cancer stemness and offers a potential target for antitumor therapy.