Breast cancer remains one of the most common solid tumors. Tumor immunosuppressive factors mainly hinder the control of tumors. We previously developed an innovative cryo-thermal therapy that was shown to significantly suppress distal metastasis and improve long-term survival in murine B16F10 melanoma and 4T1 mammary carcinoma models. However, the effect of cryo-thermal therapy on the 4T1 model was not excellent. CCL5 has been reported to help the progression of breast cancer, so in this study, CCL5-/- was used to explore the role of host-derived CCL5 after cryo-thermal therapy. CCL5-/- could not completely resist tumor development, but it significantly improved survival rates when combined with cryo-thermal therapy. Mechanically, CCL5-/- mildly decreases the percentage of MDSCs, increases DC maturation and macrophage's inflammatory function at an early stage after tumor inoculation, and later up-regulate the level of Th1 and down-regulate the level of Tregs. When combined with cryo-thermal therapy, CCL5-/- dramatically down-regulated the proportion of MDSCs and induced full M1 macrophage polarization, which further promoted Th1 differentiation and the cytotoxicity of CD8+ T cells. Our results indicated that CCL5-/- contributed to cryo-thermal-triggered, long-lasting anti-tumor memory immunity. The combination of cryo-thermal therapy and CCL5 blockades might extend the survival rates of patients with aggressive breast cancer.