Mechanistically, inhibition of HIF-2α effectively attenuates the stemness phenotypes through inactivating the PI3K/AKT/CD44 pathway.926 Acidosis, a hallmark of the tumor microenvironment, acts as a promoting factor for the stemness phenotype in melanoma, prostate cancer, colorectal cancer, and gastric cancer.927 The extracellular acidic microenvironment may become another promising target for the treatment of CSCs. Here, AKT1 is linked to melanoma.