Immunotherapy has pioneered a new era of tumor treatment, in which the immune checkpoint blockade (ICB) exerts significant superiority in overcoming tumor immune escape. However, the formation of an immune-suppressive tumor microenvironment (TME) and the lack of effective activation of the immune response have become major obstacles limiting its development. Emerging reports indicate that cancer stem cells (CSCs) potentially play important roles in treatment resistance and progressive relapse, while current research is usually focused on CSCs themselves. In this review, we mainly emphasize the collusions between CSCs and tumor-infiltrating immune cells. We focus on the summary of CSC-immune cell crosstalk signaling pathways in ICB resistance and highlight the application of targeted drugs to improve the ICB response. K E Y W O R D S cancer immunotherapy, cancer stem cell, immune cell, tumor microenvironment 1 | BACKGROUNDThe tumor microenvironment (TME) regulates the fate of cancer stem cells (CSCs). [1][2][3] It is generally believed that the TME is immunosuppressive, 4-7 while immunotherapy breaks the barriers to tumor therapy by reawakening the body's antitumor immune response that specifically kills tumor cells. 8,9 In particular, the immune checkpoint blockade (ICB), represented by programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA4), has shown a promising therapeutic effect. However, only approximately 20% of patients have a good objective response rate after receiving ICB, and most of them have hereditary resistance (primary resistance) or fail to achieve good long-term results after a period of treatment due to the development of treatment resistance or multiple complications (acquired resistance). [10][11][12][13][14][15][16][17] Therefore, the investigation of the mechanism of resistance to ICB has become an urgent issue.Emerging reports indicate that CSCs play important roles in ICB resistance. CSCs are a primitive cell population that maintains