Background: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer in adults and stands out as one of the most vascularized and immune-infiltrated solid tumors. Overproduction of vascular endothelial growth factor A promotes uncontrolled growth of abnormal vessels and immunosuppression, and the tumor microenvironment (TME) has a prominent role in disease progression, drug targeting and drug response, and for patient outcome.

Methods: Studies of experimental models, large-scale omics approaches, and patient prognosis and therapy prediction, using gene expression signatures and tissue biomarker analysis, have been reviewed for enhanced understanding of the endothelium in ccRCC and the interplay with the surrounding TME.

Results: Preclinical and clinical studies have discovered molecular mechanisms of endothelial cross-talk of relevance for disease progression, patient prognosis, and therapy prediction. There is, however, a lack of representative ccRCC experimental models. Omics approaches have identified clinically relevant subsets of angiogenic and immune-infiltrated tumors with distinct molecular signatures and distinct endothelial cell and immune cell populations in patients.

Conclusions: Recent genetically engineered ccRCC mouse models together with emerging evidence from single cell RNA sequencing data open up for future validation studies, including multiplex imaging of ccRCC patient cohorts. These studies are of importance for therapy benefit and personalized treatment of ccRCC patients.