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The study was designed to evaluate the efficiency of microwave ablation (MWA) in combination with anti-programmed death receptor 1 (anti-PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in renal cell carcinoma (RCC) treatment. After tumors were established on C57/BL6 mice, MWA treatment and/or immune checkpoint inhibitor (ICI) treatment to the mice were performed. Tumor volume was recorded every 7 days. A rechallenge test was conducted on mice with tumors in the left kidney to explore the systemic establishment of antitumor immunity on day 7. In this study, during the 21-day observation period, tumors were continued to grow in all groups. However, compared with the tumor growth rate in MWA or control group, the rate in the ICI or MWA+ICI groups was decreased. Moreover, the population of CD8+T-cells was increased only in the MWA+ICI group, while that of regulatory T cells was decreased in the MWA, ICI, and MWA+ICI groups. Additionally, the MWA+ICI group had the highest interferon-γ level among all groups. Furthermore, histopathological examination revealed that CTLA-4 expression in distant tumors was reduced in the ICI and MWA + ICI groups. MWA treatment increased PD-L1/PD-1 expression; however, after the combination treatment with ICI, PD-L1/PD-1 expression was decreased. According to the rechallenge test, mice (16.7%) in the MWA group, ICI group (50%), and MWA+ICI group (66.7%) exhibited successful tumor rejection, whereas no mice in the control group exhibited the capability of tumor rejection. Overall, the systemic antitumor immunity induced by MWA was boosted when combined with anti-PD-1/CTLA-4 treatment in an RCC murine model. [ABSTRACT FROM AUTHOR]