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Endoplasmic reticulum stress signals in the tumour and its microenvironment

Abstract

Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.

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Fig. 1: Inducers of endoplasmic reticulum stress in the tumour microenvironment.
Fig. 2: The magnitude of endoplasmic reticulum stress and its differential outcomes in malignant cells.
Fig. 3: Integration of oncogenic programmes and endoplasmic reticulum stress responses in the cancer cell.
Fig. 4: Immunomodulatory effects of endoplasmic reticulum stress signals in the tumour microenvironment.

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Acknowledgements

X.C. has been supported by the National Institutes of Health (NIH) (R37CA228304, P50CA186784 and R01HL146642), the US Department of Defense Congressionally Directed Medical Research Programs (W81XWH1910524), the American Cancer Society (RSG-18-181-01-TBE), the Cancer Prevention and Research Institute of Texas (RR150009 CPRIT Scholar in Cancer Research award) and Susan G. Komen for the Cure (CCR16380871). J.R.C.-R. has been supported by the NIH (R01NS114653 and R21CA248106), the US Department of Defense Ovarian Cancer Research Program (W81XWH-16-1-0438 and W81XWH-20-1-0191), Stand Up to Cancer (SU2C-AACR-IRG-03-16 and SU2C-AACR-PS24), the Pershing Square Sohn Cancer Research Alliance, the Mary Kay Foundation, the Daedalus Fund for Innovation, the Mark Foundation for Cancer Research ASPIRE Award and the Wade F. B. Thompson/Cancer Research Institute CLIP grant. The authors apologize to colleagues whose work is not cited in this Review due to space limitations.

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X.C. and J.R.C.-R. both researched data for the article, substantially contributed to discussion of the content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Xi Chen or Juan R. Cubillos-Ruiz.

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Competing interests

X.C. and J.R.C.-R. hold patents on the use of ER stress and UPR modulators for cancer therapy. X.C. reports research funding from Fosun Pharma.

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Nature Reviews Cancer thanks E. Chevet, C. Koumenis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Proteostasis

The regulation of a balanced and functional proteome.

Isomerization

The transformation of a molecule into a different isomer.

Hypoxia

A low level of oxygen tension.

Integrated stress response

(ISR). An adaptive signalling pathway activated by various forms of cellular stress, including endoplasmic reticulum stress, which helps maintain cellular integrity under unfavourable conditions such as nutrient restriction and oxidative stress.

Reactive oxygen species

(ROS). A natural by-product of the metabolism of oxygen that is more reactive than molecular oxygen.

ER-associated protein degradation

(ERAD). A pathway that targets misfolded proteins in the endoplasmic reticulum (ER) for ubiquitylation and degradation by the proteasome in the cytoplasm.

Autophagy

A regulated cellular process that delivers dysfunctional cellular constituents to the lysosomes for degradation and recycling.

Electron transport chain

(ETC). A series of enzymatic reactions occurring in the inner mitochondrial membrane that shuttles electrons from NADH and FADH2 to oxygen. During this process, protons pumped from the mitochondrial matrix to the intermembrane space are used to produce ATP.

Fatty acid β-oxidation

(FAO; also known as β-oxidation). The breakdown of fatty acids to generate acetyl-CoA, which is incorporated into the tricarboxylic acid (TCA) cycle.

Pattern recognition receptors

(PRRs). Germline-encoded proteins that sense invading pathogens or endogenous damage signals to initiate and regulate immune responses.

Glycolysis

The oxygen-independent metabolic pathway that converts glucose into pyruvate.

Regulated IRE1-dependent decay of RNA

(RIDD). The mechanism of microRNA or mRNA degradation caused by hyperactivation of the ribonuclease domain of inositol-requiring enzyme 1α (IRE1α).

Damage-associated molecular patterns

(DAMPs). Host-derived molecules that can initiate and drive a non-infectious inflammatory response. By contrast, pathogen-associated molecular patterns are molecules derived from an infectious non-self-entity, which also stimulate an inflammatory response.

Epithelial-to-mesenchymal transition

(EMT). A cellular developmental process by which epithelial cells acquire a mesenchymal-like phenotype. This process is accompanied by the loss of cell adhesion properties and augmented motility, and is therefore exploited by cancer cells to metastasize.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of immune cells from the myeloid lineage with relatively immature but potent immunosuppressive phenotypes. MDSCs are classified into two major subtypes: monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (polymorphonuclear (PMN)-MDSCs).

Acidosis

A process that increases acidity in the blood and other tissues.

Peroxynitrites

(PNTs). Powerful oxidants produced by the reaction between nitric oxide and superoxide radicals that cause lipid peroxidation, as well as protein and DNA damage.

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Chen, X., Cubillos-Ruiz, J.R. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer 21, 71–88 (2021). https://doi.org/10.1038/s41568-020-00312-2

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