Abstract

As the first compartment of the protein secretory pathway, the endoplasmic reticulum (ER) acts as a protein synthesis factory, maintaining proteostasis and ER homeostasis. However, a variety of intrinsic and extrinsic perturbations, such as cancer, can disrupt the homeostasis and result in a large accumulation of misfolded/unfolded proteins in the ER lumen, thereby provoking a specific cellular state addressed as “ER stress”. Then the unfolded protein response (UPR), an adaptive signaling pathway, is triggered to address the stress and restore the homeostasis. A novel aspect of ER stress is that it can be transmitted from cancer cells to tumor-infiltrating myeloid cells through certain cancer cell-released soluble factors, which is termed as transmissible ER stress (TERS) or ER stress resonance (ERSR). In this review, we provide a comprehensive overview of the link between cancer and ER stress as well as the possible soluble factors mediating TERS. We further elaborate the cell-extrinsic effects of TERS on tumor immunity, and how it indirectly modulates cancer development and progression, which is expected to add a new dimension to anticancer therapy.

Highlights

  • The endoplasmic reticulum (ER) is an intracellular membranous organelle

  • As an adaptive signaling pathway, the unfolded protein response (UPR) is Transmissible Endoplasmic Reticulum Stress predominantly controlled by three transmembrane ER stress sensors: activating transcription factor 6 (ATF6), inositolrequiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) (Zheng et al, 2016)

  • If the UPR fails to get rid of the stress, the UPR signals may switch from pro-survival to prodeath, including apoptosis, necroptosis and autophagic cell death (Sano and Reed, 2013; Hetz and Papa, 2018; Kim and Kim, 2018; Almanza et al, 2019)

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Summary

INTRODUCTION

As the first compartment of the protein secretory pathway, the ER acts as a protein synthesis factory It is involved in the production, folding, modification, maturation, quality control and degradation of approximately one-third of all cellular proteins, and makes certain that only properly folded proteins can be transported to their intracellular or extracellular sites of action (Braakman and Bulleid, 2011; Stefan et al, 2011). Active ATF6 will translocate to the Golgi apparatus, while active IRE1 and PERK will subsequently activate downstream signaling cascades, driving mutually reinforcing signaling pathways for a common purpose: to initiate corrective measures to reestablish protein homeostasis and promote cell survival (Ye et al, 2000; Shen et al, 2002; Hetz, 2012; Sano and Reed, 2013; Frakes and Dillin, 2017). If the UPR fails to get rid of the stress, the UPR signals may switch from pro-survival to prodeath, including apoptosis, necroptosis and autophagic cell death (Sano and Reed, 2013; Hetz and Papa, 2018; Kim and Kim, 2018; Almanza et al, 2019)

CANCER AND ER STRESS
TRANSMISSIBLE ENDOPLASMIC RETICULUM STRESS
THE EFFECTS OF TERS ON TUMOR IMMUNITY
Immunosuppressive Effects
CONCLUDING REMARKS AND FUTURE PERSPECTIVES
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