Endoplasmic Reticulum Stress Signals in the Tumour and Its Microenvironment

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2020 Nov 20

PMID 33214692

Citations 417

Authors

Xi Chen

Juan R Cubillos-Ruiz

Affiliations

Soon will be listed here.

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.

Citing Articles

MLKL as an emerging machinery for modulating organelle dynamics: regulatory mechanisms, pathophysiological significance, and targeted therapeutics.

Wang Y, Wei W, Zhang Y, Miao J, Bao X, Lu C Front Pharmacol. 2025; 16:1512968.

PMID: 40070567 PMC: 11893596. DOI: 10.3389/fphar.2025.1512968.

Dys-regulated phosphatidylserine externalization as a cell intrinsic immune escape mechanism in cancer.

Pulica R, Aquib A, Varsanyi C, Gadiyar V, Wang Z, Frederick T Cell Commun Signal. 2025; 23(1):131.

PMID: 40069722 PMC: 11900106. DOI: 10.1186/s12964-025-02090-6.

Suppression of stress granule formation is a vulnerability imposed by mutant p53.

Thoenen E, Ranjan A, Parrales A, Nishikawa S, Dixon D, Oka S Nat Commun. 2025; 16(1):2365.

PMID: 40064891 PMC: 11894096. DOI: 10.1038/s41467-025-57539-6.

Subcellular Organelle Targeting as a Novel Approach to Combat Tumor Metastasis.

Liu Z, Liu Y, Kang X, Li L, Xiang Y Pharmaceutics. 2025; 17(2).

PMID: 40006565 PMC: 11859411. DOI: 10.3390/pharmaceutics17020198.

Licochalcone A Induces Uterine Leiomyoma Cell Apoptosis via the ROS-Mediated JNK Activation of the GRP78/NRF2 Pathway In Vitro and In Vivo.

Chien H, Hu H, Tsai S, Lin C, Yang S, Chen J Antioxidants (Basel). 2025; 14(2).

PMID: 40002335 PMC: 11851460. DOI: 10.3390/antiox14020148.

References

Hetz C, Zhang K, Kaufman R . Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020; 21(8):421-438. PMC: 8867924. DOI: 10.1038/s41580-020-0250-z. View

Wang M, Wey S, Zhang Y, Ye R, Lee A . Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal. 2009; 11(9):2307-16. PMC: 2819800. DOI: 10.1089/ars.2009.2485. View

Walter P, Ron D . The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011; 334(6059):1081-6. DOI: 10.1126/science.1209038. View

Lee A, Iwakoshi N, Anderson K, Glimcher L . Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A. 2003; 100(17):9946-51. PMC: 187896. DOI: 10.1073/pnas.1334037100. View

Iwawaki T, Akai R, Kohno K, Miura M . A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat Med. 2004; 10(1):98-102. DOI: 10.1038/nm970. View

Merksamer P, Trusina A, Papa F . Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions. Cell. 2008; 135(5):933-47. PMC: 2739138. DOI: 10.1016/j.cell.2008.10.011. View

Spiotto M, Banh A, Papandreou I, Cao H, Galvez M, Gurtner G . Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth. Cancer Res. 2009; 70(1):78-88. PMC: 2943832. DOI: 10.1158/0008-5472.CAN-09-2747. View

Keith B, Simon M . Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007; 129(3):465-72. PMC: 3150586. DOI: 10.1016/j.cell.2007.04.019. View

Koumenis C . ER stress, hypoxia tolerance and tumor progression. Curr Mol Med. 2006; 6(1):55-69. DOI: 10.2174/156652406775574604. View

10.

Kaelin Jr W, Ratcliffe P . Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008; 30(4):393-402. DOI: 10.1016/j.molcel.2008.04.009. View

11.

Jiang D, Niwa M, Koong A . Targeting the IRE1α-XBP1 branch of the unfolded protein response in human diseases. Semin Cancer Biol. 2015; 33:48-56. PMC: 4523453. DOI: 10.1016/j.semcancer.2015.04.010. View

12.

Koritzinsky M, Levitin F, van den Beucken T, Rumantir R, Harding N, Chu K . Two phases of disulfide bond formation have differing requirements for oxygen. J Cell Biol. 2013; 203(4):615-27. PMC: 3840938. DOI: 10.1083/jcb.201307185. View

13.

May D, Itin A, Gal O, Kalinski H, Feinstein E, Keshet E . Ero1-L alpha plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer. Oncogene. 2004; 24(6):1011-20. DOI: 10.1038/sj.onc.1208325. View

14.

Young R, Ackerman D, Quinn Z, Mancuso A, Gruber M, Liu L . Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 2013; 27(10):1115-31. PMC: 3672646. DOI: 10.1101/gad.198630.112. View

15.

Koumenis C, Wouters B . "Translating" tumor hypoxia: unfolded protein response (UPR)-dependent and UPR-independent pathways. Mol Cancer Res. 2006; 4(7):423-36. DOI: 10.1158/1541-7786.MCR-06-0150. View

16.

Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt M, Hatziapostolou M . XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature. 2014; 508(7494):103-107. PMC: 4105133. DOI: 10.1038/nature13119. View

17.

Denzel M, Antebi A . Hexosamine pathway and (ER) protein quality control. Curr Opin Cell Biol. 2014; 33:14-8. DOI: 10.1016/j.ceb.2014.10.001. View

18.

Braakman I, Bulleid N . Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem. 2011; 80:71-99. DOI: 10.1146/annurev-biochem-062209-093836. View

19.

Moore C, Omikorede O, Gomez E, Willars G, Herbert T . PERK activation at low glucose concentration is mediated by SERCA pump inhibition and confers preemptive cytoprotection to pancreatic β-cells. Mol Endocrinol. 2011; 25(2):315-26. PMC: 3070211. DOI: 10.1210/me.2010-0309. View

20.

Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman A . The integrated stress response. EMBO Rep. 2016; 17(10):1374-1395. PMC: 5048378. DOI: 10.15252/embr.201642195. View