Simple SummaryIntegrins play key roles in mediating cell adhesion and delivering chemical and mechanical signals to the interior of the cell. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Integrin signaling dysregulation can be a major factor in the development of tumors, and it is involved in the processes of the malignant plasticity of the epithelium, the reactivation of metastasis, and resistance to therapeutic interventions. Here, we describe the current understanding of the α6-integrin subunit (ITGA6, also known as CD49f and/or VLA6; encoded by the geneitga6) in cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnostic biomarker, are discussed. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel therapeutic target.AbstractOver the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the geneitga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes.