The Unfolded Protein Response in Immunogenic Cell Death and Cancer Immunotherapy

The ER is a key organelle in cell physiology, and it evolved as an elaborated signaling pathway to cope with life-threatening perturbations of its homeostatic state. This process, called the UPR, is exploited by cancer cells to survive in their microenvironment and to promote tumor progression. Many approaches have been investigated to inhibit or exacerbate UPR to kill cancer cells. Among these, a defined set of agents or procedures can induce a form of ER stress-mediated cancer cell death that is immunogenic (the so-called ICD), generating an effective antitumor immunity. ICD is characterized by a spatiotemporally defined emission of DAMPs that establish a productive interface with immune cells. Combinatorial strategies based on ICD and immune checkpoint blockade are currently being investigated. The unfolded protein response (UPR) is a conserved pathway that is stimulated when endoplasmic reticulum (ER) proteostasis is disturbed or lost. Accumulating evidence indicates that chronic activation of the UPR supports the main hallmarks of cancer by favoring cancer cell-autonomous and nonautonomous processes, which ultimately foster the immunosuppressive and protumorigenic microenvironment. However, certain forms of therapy-induced ER stress can elicit immunogenic cancer cell death (ICD), which enables the release of key immunostimulatory or danger signals, eventually driving efficient antitumor immunity. In this review, after a brief discussion of the interplay between ER stress and protumorigenic inflammation, we review the relevance of therapy-mediated ER stress pathways in evoking ICD and how they could be used to optimize current immunotherapy approaches against cancer. The unfolded protein response (UPR) is a conserved pathway that is stimulated when endoplasmic reticulum (ER) proteostasis is disturbed or lost. Accumulating evidence indicates that chronic activation of the UPR supports the main hallmarks of cancer by favoring cancer cell-autonomous and nonautonomous processes, which ultimately foster the immunosuppressive and protumorigenic microenvironment. However, certain forms of therapy-induced ER stress can elicit immunogenic cancer cell death (ICD), which enables the release of key immunostimulatory or danger signals, eventually driving efficient antitumor immunity. In this review, after a brief discussion of the interplay between ER stress and protumorigenic inflammation, we review the relevance of therapy-mediated ER stress pathways in evoking ICD and how they could be used to optimize current immunotherapy approaches against cancer.