We demonstrate that ALDH3A1 activity and expression in melanoma and NSCLC cells regulate their stem cell and mesenchymal phenotype, which are closely associated with stemness and immune escape, modulating the levels of PD-L1 expression, reprogramming the tumor microenvironment through the release of immunosuppressive and pro-inflammatory mediators, and the inhibition of T cell proliferation. The gene discussed is CD274; the disease is melanoma.