Since the early phases of development of immunotherapy in mRCC, tremendous efforts have been made towards understanding the biology of the tumor microenvironment (TME) to help identify candidate biomarkers, such as immunohistochemistry (IHC) expression of PD-L1, tumor mutational burden (TMB), polybromo-1 gene (PBRM1) mutations, human endogenous retroviruses (hERVs), gastrointestinal microbiota, sarcomatoid histology, and the neutrophil to lymphocyte ratio (NLR). The gene discussed is CD274; the disease is neoplasm.