The endoplasmic reticulum (ER) is an intracellular membranous organelle. 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). Hence, the ER is closely associated with the maintenance of proteostasis and cellular homeostasis. However, a specific cellular state called “ER stress” will be triggered when ER homeostasis is disrupted by various intrinsic or extrinsic perturbations, including cancer (Papaioannou and Chevet, 2018), obesity (Hetz et al., 2020), neurodegeneration (Riaz et al., 2020), Alzheimer’s disease (Uddin et al., 2020), diabetes (Brooks-Worrell and Palmer, 2019), inflammation (Li et al., 2020), reactive oxygen species (ROS) production (Ochoa et al., 2018), etc.

In response to ER stress, the unfolded protein response (UPR) then will be triggered to overcome the stress and restore proteostasis and ER homeostasis by transcriptionally and translationally decreasing protein synthesis, increasing ER protein folding capacity and degrading the misfolded/unfolded proteins (Hetz, 2012). As an adaptive signaling pathway, the UPR is predominantly controlled by three transmembrane ER stress sensors: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) (Zheng et al., 2016). The ER luminal domains of all the three sensors normally bind to the ER-resident chaperone, binding immunoglobulin protein (BiP), also known as glucose-regulated protein 78 (GRP78), locking them in monomeric, inactive states (Bertolotti et al., 2000; Shen et al., 2002). The three sensors will be released and activated when accumulational misfolded/unfolded proteins in the ER lumen competitively engage BiP (Pincus et al., 2010; Kopp et al., 2019). Then 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). Nevertheless, if the UPR fails to get rid of the stress, then the UPR signals may switch from pro-survival to pro-death, including apoptosis, necroptosis and autophagic cell death (Sano and Reed, 2013; Hetz and Papa, 2018; Kim and Kim, 2018; Almanza et al., 2019).

As ER stress and the UPR have been reported in many kinds of cancers, it is widely acknowledged that cancer is one of the intrinsic ER perturbations that can result in ER stress as well as constitutive activation of the UPR signaling pathways (Hanahan and Weinberg, 2011; Wang and Kaufman, 2014; Kaneko et al., 2017). ER stress within cancer cells is initiated and amplified through multiple cell-intrinsic and cell-extrinsic mechanisms. First of all, high genetic instability and numerous non-synonymous mutations of cancers such as melanoma (Piwocka et al., 2006) and lung cancers (Volmer et al., 2013) can straightly destroy the folding capacity of proteins. Besides, high protein demand of uncontrollably and rapidly growing cancer cells can aggravate the burden of ER protein folding capacity, especially for some highly secretory cancers (Obeng et al., 2006; Holderfield et al., 2014). Furthermore, hypoxia, starvation, and lactic acidosis resulting from the depletion of oxygen and nutrients in the tumor microenvironment (TME) can also fuel ER stress (Vaupel et al., 1989; Giampietri et al., 2015; Chipurupalli et al., 2019; Xia et al., 2019). Notably, it is reported that several anticancer drugs can bring about ER stress in vitro, whose effects in vivo are unclear yet (Ma et al., 2014; Jeon et al., 2015; Pozzi et al., 2016).

In fact, there is an intimate interaction between cancer and ER stress, in other words, cancer can result in ER stress, which in turn can alter cancer development and progression. First of all, if cells can successfully impose restrictions on pro-apoptotic UPR outputs, IRE1 and PERK signaling pathways will facilitate the survival and growth of cancer cells under hypoxia and nutrient deprivation in vivo (Koumenis et al., 2002; Romero-Ramirez et al., 2004; Chen et al., 2014). Moreover, inducing intracellular autophagy can also sustain the survival of cancer cells. It is demonstrated that PERK-mediated autophagy is required to resist anoikis, a type of cell death as a result of extracellular matrix (ECM) detachment (Avivar-Valderas et al., 2011; Dey et al., 2015). Secondly, PERK induces epithelial-to-mesenchymal transition (EMT), a significant biological process for epithelial-derived malignant tumor cells to acquire the ability to migrate, invade and form tumorsphere, by silencing E-cadherin or overexpressing Twist, which was verified to be inhibited by a small-molecule PERK inhibitor (Feng et al., 2014; Dey et al., 2015). In addition, it is suggested that the PERK/eIF2α arm of the UPR enhances migration and invasion through induction of metastasis-associated LAMP3 in vivo and in vitro (Mujcic et al., 2013). Furthermore, multiple branches of the UPR are found contributive to a p38-dependent program of anti-proliferative dormancy of cancer cells during metastasis, which insulates these disseminated cells from adverse microenvironmental conditions such as hypoxia, glucose deprivation and even many anticancer drugs that rely on active proliferation (Ranganathan et al., 2006; Schewe and Aguirre-Ghiso, 2008; Bartkowiak et al., 2015). Thirdly, the UPR signaling pathways provide rapidly growing solid cancers with essential vascularization, which is conducive to providing adequate oxygen and nutrients while removing harmful substances. PERK translationally upregulates the vessel growth and stabilization factors: type 1 collagen inducible protein (VCIP) and platelet-derived growth factor receptor β (PDGFRβ) (Blais et al., 2006). Similarly, IRE1/XBP1, PERK/ATF4 and ATF6 can transcriptionally upregulate vascular endothelial growth factor A (VEGFA) under hypoxia and glucose deprivation (Ghosh et al., 2010). IRE1 also maintains the production of a broad variety of pro-angiogenic cytokines in malignant glioma (Auf et al., 2010). At last, ER stress likely leads to eventual drug resistance, for several anticancer drugs can induce autophagy, through which the survival of cancer cells may be achieved (Sui et al., 2013). For instance, PERK and IRE1/JNK signaling pathways can sustain autophagy, and this way gives rise to sorafenib resistance in hepatocellular carcinoma cell lines (Ogata et al., 2006; Shi et al., 2011). To sum up, the UPR will facilitate the survival, metastatic capacity, angiogenesis and drug resistance of cancer cells if ER stress is addressed in time. On the other hand, the UPR signaling will switch from pro-survival to pro-death if severe and unresolved ER stress leads to a huge accumulation of the misfolded/unfolded proteins, which is far beyond ER’s capacity to adapt and self-regulate (Hetz et al., 2015).

As a consequence, ER stress imposes a bidirectional regulation effect on cancer development and progression: both tumor-supporting and tumor-suppressive roles. However, current molecular insights into the mechanisms that allow the UPR signaling switch from pro-survival to pro-death pathways are still insufficient.

In addition to directly influencing the behaviors of cancer cells, ER stress is also involved in intercellular communication between tumor cells and non-tumor cells. Mahadevan et al. (2011) demonstrated for the first time that certain “soluble factors” released from prostate cancer cells undergoing ER stress can induce similar ER stress in bone marrow-derived myeloid cells, which is termed as transmissible ER stress (TERS). Subsequent studies further confirmed that TERS occurs in information communication between ER stressed cancers cells and other cancer cells or tumor-infiltrating immune cells such as tumor-associated macrophages (TAMs) (Urra et al., 2016; Rodvold et al., 2017). Hence, we propose a new concept of ER stress resonance (ERSR) to better understand the transfer of ER stress from a single primary cell to surrounding secondary cells through certain soluble factors. Inducing ER stress within these recipient cells can impede protective anti-tumor immunity while promoting survival and drug resistance in cancer cells and pro-inflammatory responses of immune cells, thus contributing to cancer development and progression (Mahadevan et al., 2012; Cullen et al., 2013; Cubillos-Ruiz et al., 2017; Rodvold et al., 2017; So, 2018; Di Conza and Ho, 2020). To date, limited evidence suggests that the soluble factors may be tumor-derived extracellular vesicles (TEVs), proteins or even lactic acid (Figure 1).

In the past few decades, the effects of ER stress on cancer cells have been described in detail, but the causes and effects of TERS from tumor cells to neighboring non-tumor cells are only beginning to be investigated. Here, we will briefly discuss the effects of TERS on tumor-infiltrating immune cells and inflammatory responses of these cells in the TME, as well as how it indirectly influences cancer development and progression.

There is an intimate interaction between cancer and ER stress. Cancer is one of the intrinsic ER perturbations that can give rise to ER stress and the constitutive activation of the UPR signals. In return, ER stress imposes a bidirectional regulation effect on cancer development and progression: both tumor-supporting and tumor-suppressive roles. Specifically, the UPR promotes the survival, metastatic capacity, angiogenesis and drug resistance of cancer cells if ER stress is overcame in time, whereas severe and lethal ER stress induces cancer cell death. An intriguing question posed by the UPR signaling switching from pro-survival to pro-death is what the threshold between two distinct-different regulatory signals is. Further research is required to answer this question.

In addition to directly regulating cancer cell phenotype, ER stress can be transmitted from cancer cells to neighboring tumor-infiltrating immune cells within the TME through certain cancer cell-released soluble factors, resulting in TERS among the two types of cells. Currently, limited evidence suggests the soluble factors may be certain functional cargo in TEVs, proteins or even lactic acid. Of note, TERS is found to play an immunosuppressive role in tumor-infiltrating immune cells, and these cells display pro-inflammatory/suppressive responses, which indirectly facilitates cancer development and progression. Hence, it is of paramount importance to further elucidate molecular mechanisms of TERS, since the soluble factors mediating TERS may constitute key points to improve the efficacy of broad-spectrum anticancer therapies.

ZJ wrote the manuscript. GZ, LH, YY, and CW collected the related references and edited the manuscript. YL provided guidance and revised the manuscript. All authors approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.