Cell surface GRP78 and the UPR pathway as novel promising therapeutic targets in cancer: an insight into the treatment of acute leukemia by using GRP78-CART cells.

Around 70s decade, the discovery of endoplasmic reticulum (ER) chaperones as central regulators of protein folding and quality control set a new paradigm for the understanding of cellular homeostasis. With the arrival of global proteomic approaches, several ER chaperones, including the 78-kDa glucose-regulated protein (GRP78), were unexpectedly found at the cell surface of cancer cells, linking activation of the unfolded protein response (UPR) to tumor biology. Current knowledge suggests that cell surface GRP78 (csGRP78) is a promising therapeutic biomarker, as it is virtually absent on normal cells but enriched on multiple cancers, particularly leukemias. This review summarizes the roles of the three main UPR regulators-IRE1, ATF6, and PERK-and their crosstalk with csGRP78 in leukemia, emphasizing how this network can promote survival or apoptosis. Finally, recent preclinical studies using GRP78-directed CAR-T cells are discussed, highlighting csGRP78 and the UPR pathway as attractive targets for leukemia immunotherapy.