Simple SummaryThe central nervous system constitutes a unique microenvironment to which access is highly restricted. However, immune cells enter as part of their normal routine surveillance, and some cancers, including leukemia in children, also spread to this site constituting a major challenge to therapy. Because of the restricted nature of the central nervous system, these cells are expected to make use of a defined set of adhesion molecules that will allow entry and residence. Integrins are a family of adhesion molecules, studied for decades in both normal immune cells and cancer cells. Here, we scrutinize the available knowledge to see if the same integrins are used by different cell types entering the central nervous system. By highlighting similarities between dissimilar cells and identifying gaps in our current understanding, the present review could be a helpful resource of ideas for future cancer research.AbstractAcute lymphoblastic leukemia (ALL) disseminates with high prevalence to the central nervous system (CNS) in a process resembling aspects of the CNS surveillance of normal immune cells as well as aspects of brain metastasis from solid cancers. Importantly, inside the CNS, the ALL blasts are typically confined within the cerebrospinal fluid (CSF)-filled cavities of the subarachnoid space, which they use as a sanctuary protected from both chemotherapy and immune cells. At present, high cumulative doses of intrathecal chemotherapy are administered to patients, but this is associated with neurotoxicity and CNS relapse still occurs. Thus, it is imperative to identify markers and novel therapy targets specific to CNS ALL. Integrins represent a family of adhesion molecules involved in cell-cell and cell-matrix interactions, implicated in the adhesion and migration of metastatic cancer cells, normal immune cells, and leukemic blasts. The ability of integrins to also facilitate cell-adhesion mediated drug resistance, combined with recent discoveries of integrin-dependent routes of leukemic cells into the CNS, have sparked a renewed interest in integrins as markers and therapeutic targets in CNS leukemia. Here, we review the roles of integrins in CNS surveillance by normal lymphocytes, dissemination to the CNS by ALL cells, and brain metastasis from solid cancers. Furthermore, we discuss whether ALL dissemination to the CNS abides by known hallmarks of metastasis, and the potential roles of integrins in this context.