The “Yin and Yang” of Unfolded Protein Response in Cancer and Immunogenic Cell Death

Abstract

Physiological and pathological burdens that perturb endoplasmic reticulum homeostasis activate the unfolded protein response (UPR), a conserved cytosol-to-nucleus signaling pathway that aims to reinstate the vital biosynthetic and secretory capacity of the ER. Disrupted ER homeostasis, causing maladaptive UPR signaling, is an emerging trait of cancer cells. Maladaptive UPR sustains oncogene-driven reprogramming of proteostasis and metabolism and fosters proinflammatory pathways promoting tissue repair and protumorigenic immune responses. However, when cancer cells are exposed to conditions causing irreparable ER homeostasis, such as those elicited by anticancer therapies, the UPR switches from a survival to a cell death program. This lethal ER stress response can elicit immunogenic cell death (ICD), a form of cell death with proinflammatory traits favoring antitumor immune responses. How UPR-driven pathways transit from a protective to a killing modality with favorable immunogenic and proinflammatory output remains unresolved. Here, we discuss key aspects of the functional dichotomy of UPR in cancer cells and how this signal can be harnessed for therapeutic benefit in the context of ICD, especially from the aspect of inflammation aroused by the UPR.

Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy

“…UPR induction acts initially as a cell protective process aimed to restore protein homeostasis. However, if the damage is excessive, UPR moves from protective-to-cytotoxic in order to eliminate dysfunctional cells [38]. Chemotherapeutic drugs, as strong inducers of stress in cancer cells, could exert their cytotoxic effect at least in part through boosting the transition from protective-to-cytotoxic UPR.…”

Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy

“…ICD is characterized by spatiotemporal surface rearrangements of danger molecules and DAMPs that occur simultaneously with cell death. DAMPs are endogenous molecules that have housekeeping functions in unstressed cells but act as danger signals sensed by the immune system when exposed to cellular stress or injury [ 170 ]. They stimulate the adaptive immune system by binding to homologous receptors on innate immune cells such as dendritic cells (DCs), eliciting tumor antigen-specific CD8 T cell-mediated immune responses, thereby eliminating residual cancer cells and establishing immunological memory.…”

Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy

“…In tumors, diverse genetic and transcriptional abnormalities, metabolic alterations, and microenvironmental perturbations such as oxidative stress, oxygen limitation, nutrient deprivation, and high metabolic demand, can perturb adaptation of the unfold protein response (UPR) and provoke sustained ER stress sensors and activation of pathways such as PRKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) to endow tumor progression. , Productive or nonlethal ER stress responses restore cellular homeostasis to promote cell adaptation to stress and maintain survival. On the contrary, irreparable persistant ER stress can lead to cell death. − Thereby, the provoked ER stress often operates as a double-edged sword to determine cell function and would lead tumor to different fates. Aberrant activation of ER stress sensors and oxidative stress and their downstream components have therefore emerged as vital regulators of tumor growth and metastasis as well as response to cancer therapy. ,,, ER-focused stress responses would elicit intense and lethal ER stress to instigate ICD for cancer therapy.…”