Endoplasmic reticulum (ER) stress is a cell state in which misfolded or unfolded proteins are aberrantly accumulated in the ER. ER stress induces an evolutionarily conserved adaptive response, named the ER stress response, that deploys a self-regulated machinery to maintain cellular proteostasis. However, compared to its well-established canonical activation mechanism, the negative feedback mechanisms regulating the ER stress response remain unclear and no accepted methods or markers have been established. Several studies have documented that both endogenous and exogenous insults can induce ER stress in cancer. Based on this evidence, small molecule inhibitors targeting ER stress response have been designed to kill cancer cells, with some of them showing excellent curative effects. Here, we review recent advances in our understanding of negative feedback of the ER stress response and compare the markers used to date. We also summarize therapeutic inhibitors targeting ER stress response and highlight the promises and challenges ahead.

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