Background: Although the contemporary role of cytoreductive nephrectomy (CN) has been significantly downsized, the role of CN in immuno-oncology era still remains. Since the efficacy of immune checkpoint inhibitor (ICI) is limited, the role of CN in combination with ICI from the perspective tumor immune microenvironment (TIME) was evaluated using murine models and hypothesized that interleukin 6 (IL-6) blockade would enhance the efficacy of ICI therapy. Methods: Low- and high-tumor burden pulmonary metastatic orthotopic murine mRCC models have been developed. Antibodies targeting PD-1, CTLA-4, and IL-6 were systemically injected through the peritoneum. Renca implanted kidney was removed in the CN performed group and the timing of CN was differentiated according to the upfront and deferred CN group. The remodeling of the TIME was analyzed by flow cytometry, immunofluorescence analysis, and measurement of cytokines. Results: Upfront CN group demonstrated significantly better survival outcomes compared to deferred CN group in low-tumor burden models, while significantly longer survival was reported in deferred CN group compared to upfront CN group in high-tumor burden models. CN modulate IL-6 levels which act as a negative regulator of myeloid-derived stem cells (MDSCs) and M2 tumor-associated macrophage (TAM). The blockade of IL-6 activated CD8+ T-cell accumulation and led to decreased expression of MDSCs and M2 TAM, which is similar to the effects on TIME by CN combined with ICI therapy. Conclusions: This study is the first animal study to demonstrate the role of CN in combination with ICI. CN decreases the production of the cytokine IL-6, increasing the anti-cancer immunity TIME through modulation of MDSC and M2 TAM. Our study provides a research basis for the significant role of IL-6 in tumor regression and highlights a novel target to improve the efficacy of immunotherapy.