The novel immune checkpoint HLA-G has unique features, including lack of expression in normal tissue, pan-cancer-specific expression, potent immune suppression through signaling with the inhibitory receptors ILT-2 and ILT-4, and its association with poor prognosis in cancer patients, making HLA-G an attractive non-self and tumor-site-agnostic target for cancer immunotherapy. This evidence concerns the gene HLA-G and cancer.