Many cancers are driven and maintained by a subpopulation of cells that display stem cell properties and are therefore referred to as cancer stem cells (CSCs).  Targeting CSCs may increase the therapeutic efficacy of current cancer treatment, particularly in the adjuvant setting. In this study, established s.c. SCC7 tumors were surgically removed followed by treatment using ALDH^high SCC7 CSC-DC vaccine, which significantly reduced local tumor relapse and prolonged animal survival. This effect was significantly augmented by simultaneous administration of anti-PD-L1 mAb. In the minimal disease setting of D5 melanoma model, ALDH^high CSC–DC vaccination significantly inhibited tumor growth and reduced spontaneous lung metastases. CCR10 and its ligands were down-regulated on ALDH^high D5 CSCs and in lung tissues respectively in animals subjected to ALDH^high D5 CSC–DC vaccination. Down-regulation of CCR10 by siRNA significantly blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from ALDH^high D5 CSC–DC vaccinated animals selectively killed the ALDH^high D5 CSCs.  B cells harvested from ALDH^high D5 CSC–DC vaccinated animals produced IgG which bound to ALDH^high D5 CSCs, resulting in their lysis via CDC. As a result, CSC-DC vaccination significantly decreased the percentage of ALDH^high cells in residual tumors by destroying cancer stem cells. These data indicate that, when used in an adjuvant setting, ALDH^high CSC–DC vaccines effectively inhibit local tumor recurrence, reduce spontaneous lung metastasis, and prolong animal survival, compared with traditional DC vaccines and that simultaneous PD-L1 blockade can significantly enhance this effect. These findings may lead to the development of novel immunotherapeutic strategies for cancer treatment via the modulation of both cellular and humoral anti-CSC immunity.