Abstract Loss of the von Hippel-Lindau (VHL) tumor suppressor gene function accounts for 70-80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation; however, how the ccRCC tumor cells interact with the immune components of the microenvironment has remained unclear. In this study we employed unbiased proteomic and genomic analyses on components of the tumor microenvironment under different conditions. We have identified the molecular and cellular mechanisms that underlie the crosstalk between VHL-deficient kidney tubule cells and macrophages with relevance to tumor-associated inflammation and ccRCC development. We demonstrate that the VHL-deficient non-cancerous kidney epithelial cells, representing the early stage of ccRCC initiation, secrete IL-6 that recruits macrophages and induces their polarization toward the pro-tumorigenic M2 phenotype in vitro and in the mouse Vhlh gene conditional knockout model. The activated human macrophages reciprocally secrete CCL18 and TGF-beta1 to stimulate epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Importantly, treatment with anti-IL-6 neutralizing antibody can rescue inflammatory, proliferative, and EMT phenotypes of Vhlh conditional knockout in vivo. Furthermore, in a human ccRCC xenograft model, exogenous human macrophages can significantly promote primary tumor growth and metastasis; and this oncogenic function is dependent on the expression of CCL18. These findings identify specific factors involved in a reciprocal crosstalk between the tumor cells and the immune components such as macrophages in the microenvironment. These results thus suggest an avenue for early intervention of ccRCC. Citation Format: Tien Hsu, Thi Ngoc Nguyen, Hieu-Huy Nguyen-Tran, Chen-Yun Chen. IL-6 and CCL18 mediate reciprocal interactions between VHL-deficient kidney cells and macrophages during development of ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB051.