Figure 3.

Tumor hypoperfusion, along with low oxygen levels, depleted nutrition, low pH (acidosis), increased liver stiffness, and an overall increased need for protein translation by rapidly proliferating tumor cells and recruitment of inflammatory cells, as well as activation of oncogenes, all induce the UPR inside tumor cells and in its microenvironment. This activation of the UPR will amplify the pro-tumoral inflammatory response and further increase activation of stellate cells, leading to fibrosis and deposition of ECM, thus inducing a vicious circle that further fuels ER stress pathways and contributes directly and indirectly to increased chemoresistance in HCC.