Summary of mechanisms and pathways of HIF-mediated drug therapy failure. HIF-1 confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. In addition, hypoxia results in a decrease in pH and creates an acidic TME. Mechanisms by which the tumor acidic microenvironment leads to MDR, including a decreased concentration of the drug caused by “ion trapping,” reduced apoptotic potential, genetic alterations (such as p53 mutations), and elevated activity of a multidrug transporter p-glycoprotein (P-gp)