Targeting ER stress in the hepatic tumor microenvironment

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer.