In this report, we address the underlying mechanisms of YY1 in the regulation of PD-L1 expression on cancer cells and determine whether its inhibition will restore not only the anti-tumor activities of CD8+ T cells but also reverse other pro-tumorigenic activities associated with YY1, such as its role in tumor cell proliferation, cell viability, tumor invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. This evidence concerns the gene YY1 and cancer.