Signaling pathways in the regulation of cancer stem cells and associated targeted therapy

Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self‐renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well‐established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor‐associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy‐resistant or ‐refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC‐directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC‐directed therapeutics, with a special focus on those with application approval or under clinical evaluation.