Most cancer immunotherapy approaches aim to stimulate cytotoxic CD8+T lymphocytes to reject tumor cells. Due to the tumor-mediated suppressive micro-environment, of which the major contributor is regulatory T cells (Tregs), promising preclinical approaches were disappointing in clinical settings. Our recent study demonstrated that transient interruption of Tregs could induce CD8+T cell responses to reject tumors in an animal model. The long-term tumor protective effect has yet not to be investigated. In this study, mice with Treg depletion rejected tumors and were rechallenged to study anti-tumor memory immune responses. The effects of major immune cell subsets on tumor protection were explored. Finally, we demonstrate that transient depletion of Tregs during primary tumor challenge can result in long-lasting protection against the tumor rechallenge. Skin-resident memory T cells (sTRM) were major factors in rejecting rechallenged tumors even when peripheral T cells were deficient. These findings highlight a promising strategy for empowering tissue-resident memory T cells for cancer prevention and immunotherapy in humans by interrupting Tregs.