Collectively, these data demonstrated that the function of HLA-G/ILT2 and PD-1/PD-L1 checkpoint in renal cell carcinoma is dicotomic, and HLA-G+/PD-L1+ tumor cells may abrogate the function of two distinct cytotoxic effector cell subsets in the tumor microenvironment. Here, HLA-G is linked to hereditary clear cell renal cell carcinoma.