Paradoxical roles of autophagy induced by the tumor microenvironment during different stages of tumor development. (a) Autophagy is induced by multiple stressors in the tumor microenvironment, including hypoxia, nutrient deprivation, inflammation, and ECM detachment. Hypoxia activates autophagy through AMPK, PERK and HIF-1a/FOXO3 signaling pathways. The AMPK pathway is also activated by nutrient deprivation. Autophagy can be also induced by ECM detachment through the Akt-mTORC1 and IKK pathways. Inflammation is another inducer of autophagy that acts through the NF-κB signal pathway. (b) Before tumorigenesis, autophagy can suppress tumor initiation by protecting normal cells and inhibiting inflammation (including inhibiting inflammasome and necrosis). In contrast, autophagy promotes tumor growth in established tumors. Autophagy can promote inflammation by favouring inflammatory cells growth. Autophagy can also protect tumor cells and provide sufficient oxygen and nutrient.