(1)Background: The exact localization of abnormally expressed the tumor microenvironment（TME）of B7-H3 which is still unclear and requires investigation. Therefore, targeted non-immunotherapy regimens, which are represented by the B7 family, have emerged as new tumor vessel specific expression markers in renal clear cell carcinoma（ccRCC）. (2)Methods: The relationship between differentially expressed genes (DEGs) and the B7 family in ccRCC samples was identified between the normal and tumor samples by treating ccRCC samples and the gene expression profiling of GSE108310. In 18 samples containing 5000 corresponding transcripts, the Differentially Expressed Genes and the pathway enrichment were dissected by R software. 43 up-regulated genes and 255 downregulated genes were selected in the Gene Expression Omnibus database. The KEGG method was applied to investigate what effects of most DEGs on phagocytosis, platelet activation, and agglutination. (3)Results: The protein interaction network map shows that the key genes, namely, the FYN, CD244, IL6, TNF, and VEGFA genes, are the most closely connected with the other genes, and combined with functional enrichment, we found that the differences in the key genes of expression in the TME are closely related to the B7 family, especially the VEGFA and B7-H3 on T cell regulation. Targeting the B7-H3 subset as a prominent biomarker for the vascular-specific expression of ccRCC cells is necessary because it providing strong support at the genetic analysis level. (4)Conclusion: The B7 family has great potential as biomarkers for ccRCC progression.