AbstractCancer stem cells (CSCs) are associated with the tumor microenvironment (TME). CSCs induce tumorigenesis, tumor recurrence and progression, and resistance to standard therapies. Indeed, CSCs pose an increasing challenge to current cancer therapy due to their stemness or self‐renewal properties. The molecular and cellular interactions between heterogeneous CSCs and surrounding TME components and tumor‐supporting immune cells show synergistic effects toward treatment failure. In the immunosuppressive TME, CSCs express various immunoregulatory proteins, growth factors, metabolites and cytokines, and also produce exosomes, a type of extracellular vesicles, to protect themselves from host immune surveillance. Among these, the identification and application of CSC‐derived exosomes could be considered for the development of therapeutic approaches to eliminate CSCs or cancer, in addition to targeting the modulators that remodel the composition of the TME, as reviewed in this study. Here, we introduce the role of CSCs and how their interaction with TME complicates immunotherapies, and then present the CSC‐based immunotherapy and the limitation of these therapies. We describe the biology and role of tumor/CSC‐derived exosomes that induce immune suppression in the TME, and finally, introduce their potentials for the development of CSC‐based targeted immunotherapy in the future.