“…This function does not originate from physiological CALR pools within the ER or ERGIC, but from an expanded pool of CALR molecules that are exposed on the membrane of cells undergoing the so-called integrated stress response (ISR), 74 a multipronged, cell-wide reaction to specific perturbations of the extracellular or intracellular microenvironment that cause (in a majority of cases) the loss of ER homeostasis. 75,76 In particular, the translocation of CALR on the outer surface of the plasma membrane, which relies on the inactivating phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α) 77 (Box 2), can be induced by a number of chemotherapeutic agents (i.e., anthracyclines, taxanes, oxaliplatin, bortezomib, PT-112, and others), [78][79][80][81][82][83][84] radiation therapy, 85,86 some variants of photodynamic therapy, [87][88][89][90][91] high hydrostatic pressure, 92,93 oncolytic peptides, [94][95][96] and oncolytic viruses, [97][98][99][100][101] among others. 102,103 Cell surface-exposed CALR delivers potent pro-phagocytic signals to APCs including DCs and their precursors, 104,105 de facto initiating the uptake of dying cells or their corpses in the context of immunostimulation.…”