Endoplasmic reticulum stress responses in anticancer immunity

Abstract

The endoplasmic reticulum (ER) has a central role in processes essential for mounting effective and durable antitumour immunity; this includes regulating protein synthesis, folding, modification and trafficking in immune cells. However, the tumour microenvironment imposes hostile conditions that disrupt ER homeostasis in both malignant and infiltrating immune cells, leading to chronic activation of the unfolded protein response (UPR). Dysregulated ER stress responses have emerged as critical modulators of cancer progression and immune escape, influencing the initiation, development and maintenance of antitumour immunity. In this Review, we examine how tumour-induced ER stress reshapes the functional landscape of immune cells within the tumour microenvironment. We highlight recent discoveries demonstrating how ER stress curtails endogenous antitumour immunity and reduces the efficacy of immunotherapies. Furthermore, we underscore novel therapeutic strategies targeting ER stress sensors or UPR components to restore immune function and enhance cancer immunotherapy outcomes. Together, this provides a comprehensive overview of the interplay between ER stress responses and antitumour immunity, emphasizing the potential of UPR-targeted interventions to improve immune control of cancer.

Fig. 1 |. Metabolic stressors disturbing ER homeostasis in the TME.

a, In cancer cells, unconjugated bile acids induce endoplasmic reticulum (ER) stress by disrupting ER homeostasis, whereas taurine-conjugated bile acids mitigate the unfolded protein response (UPR) pathway activation. Taurine restriction intensifies ER stress, activating the protein kinase RNA-like ER kinase (PERK) pathway and promoting apoptosis in cancer cells. In CD8⁺ T cells, unconjugated bile acids, particularly the secondary bile acid lithocholic acid, induces ER stress, which promotes T cell exhaustion and dysfunction in advanced hepatocellular carcinoma. When taurine is depleted from the microenvironment due to cancer cell uptake, CD8⁺ T cells exhibit exhaustion via PERK–activating transcription factor 4 (ATF4) signalling, impairing cytokine production and upregulating immune checkpoints. Question marks indicate that the mechanism remains unknown. b, Lipid imbalance in the tumour microenvironment (TME), including cholesterol and glucosylceramide accumulation, disrupts ER homeostasis. Cholesterol accumulation activates inositol-requiring enzyme 1α (IRE1α)–XBP1s, impairing CD8⁺ T cell cytotoxicity. Glucosylceramide induces lipid saturation in tumour-associated macrophages, activating detrimental IRE1α–XBP1s signalling that promotes T cell suppression. c, Carbon monoxide (CO) is often elevated in the TME due to upregulation of haem oxygenase-1, which is induced by oxidative stress and chronic UPR activation. While controlled CO administration enhances mitochondrial–ER communication (the dashed line is shown here to indicate indirect interaction), improving CD8⁺ T cell metabolic resilience and antitumour activity, high levels of CO drive immunosuppressive phenotypes. ARG1, arginase 1; BiP, binding-immunoglobulin protein (also known as GPR78); CHOP, C/EBP homologous protein; CTLA4, cytotoxic T lymphocyte protein 4; EGFR, epidermal growth factor receptor; eIF2α; eukaryotic initiation factor 2α; LAG3, lymphocyte activation gene 3; LPCAT3, lysophosphatidylcholine acyltransferase 3; PD1, programmed cell death protein 1; ROS, reactive oxygen species; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TIM3, T cell immunoglobulin and mucin-domain-containing-3.

Fig. 2 |. Immunomodulatory effects of ER stress in cancer cells.

The tumour microenvironment (TME), characterized by hypoxia, oxidative stress and nutrient deprivation, compromises the protein-folding capacity of the endoplasmic reticulum (ER), leading to the accumulation of misfolded proteins. This triggers activation of ER stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor (ATF6) in cancer cells, which can modulate antitumour immunity. a, PERK activation phosphorylates eukaryotic initiation factor 2α (eIF2α), suppressing global translation and inhibiting major histocompatibility complex I (MHC-I) expression. The loss of PERK in melanoma cells induces SEC61β-dependent paraptosis, an alternative cell death pathway characterized by vacuolation and damage to the ER and mitochondria, and triggers immunogenic cell death (ICD), promoting long-term antitumour immunity through type I interferon (IFN-I) secretion by dendritic cells. IFN-I production promotes common monocyte precursor (cMoP) recruitment to the tumour and enhances their local differentiation into dendritic cells that prime antitumour CD8⁺ T cells. b, Activation of the IRE1α–XBP1s axis in breast cancer cells promotes expression of interleukin 6 (IL-6), IL-8, C-X-C motif chemokine ligand 1 (CXCL1), granulocyte–macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-β (TGFβ). These cytokines facilitate the accumulation of cancer-associated fibroblasts and myeloid-derived suppressor cells in triple-negative breast cancer (TNBC) models, blunting immune surveillance. Generation of XBP1s by IRE1α also inhibits expression of natural killer (NK) group 2 member D (NKG2D) ligands, such as MHC-I polypeptide-related sequence A (MICA), by suppressing E2F1 that is responsible for MICA expression. Engagement of MICA would induce activating signals in NK cells and trigger NK cell-mediated cytotoxicity that eliminates cancer cells. Activation of IRE1α in melanoma cells has been shown to upregulate programmed cell death 1 ligand 1 (PDL1) expression. Similarly, in TNBC cells, ER stress was shown to enhance PDL1 stability through its interaction with the ER chaperone binding-immunoglobulin protein (BiP), but whether this is specifically mediated by IRE1α remains unclear (indicated with a dashed line). IRE1α–XBP1s also sustains expression of prostaglandin E synthase (Ptges, encoding microsomal prostaglandin E synthase-1 (mPGES1)) in lung cancer cells, enabling prostaglandin E2 (PGE₂)-driven immunosuppression in the TME. Beyond generating XBP1s, IRE1α also cleaves select mRNAs through regulated IRE1α-dependent decay (RIDD). This activity prevents double-stranded RNA (dsRNA) accumulation in docetaxel-treated TNBC cells, thus preventing Z-DNA-binding protein 1 (ZBP1)-mediated NOD-like receptor family, pyrin domain-containing 3 (NLRP3) activation and pyroptosis, a lytic, pro-inflammatory form of programmed cell death triggered by inflammasome activation. Inhibition of the IRE1α RNase domain enables pyroptosis, enhances CD8⁺ T cell infiltration, and sensitizes TNBC tumours to ICB and taxane-based chemotherapy. c, ATF6 activation in colon epithelial cells promotes a less structured mucosal layer and is therefore more permeable to bacterial penetration. This leads to microbiota dysbiosis, innate immune infiltration and inflammation, facilitating tumorigenesis. In mice expressing a constitutively active form of ATF6 (nATF6^IEC), this was shown to be mediated by myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adaptor inducing interferon-β (TRIF)-dependent signal transducer and activator 3 (STAT3) activation. This could be reversed by antibiotics, thus linking ATF6 activation to microbiome-driven immune modulation. Yet the current understanding of ATF6 in tumour-related immune regulation is limited. In mouse B16 melanoma and RAS-driven lung cancer cells, severe ER stress leads to calreticulin translocation from the ER to the cell membrane. The externalized calreticulin (ecto-CRT) is recognized by NK cells and enhances elimination of ER-stressed cancer cells, but the precise ER stress sensor mediating this process is unknown (indicated by a dashed line). HMGB1, high-mobility group box 1; moDC, monocytic-lineage inflammatory dendritic cell; TLR, toll-like receptor.

Fig. 3 |. ER stress responses in intratumoural immune cells.

a, Reactive oxygen species (ROS)-driven endoplasmic reticulum (ER) stress in tumour-infiltrating dendritic cells (DCs) leads to potent inositol-requiring enzyme 1 α (IRE1α)–XBP1s activation, causing dysregulated lipogenesis and lipid droplet accumulation that impairs antigen presentation to T cells. Abrogating IRE1α–XBP1s in tumour-infiltrating DCs enhances T cell activation and promotes antitumour immunity in ovarian cancer models. BAT3 deficiency in DCs exacerbates the unfolded protein response (UPR), suppresses co-stimulatory molecule expression and alters metabolic pathways to promote immunosuppression, which can be reversed by disabling IRE1α. Tumour-associated macrophages (TAMs) exhibit ER stress-driven activation of IRE1α–XBP1s, supporting tumour growth through the secretion of interleukin-4 (IL-4), IL-6, vascular endothelial growth factor (VEGFA), tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA) and thrombospondin 1 (THBS1). Protein kinase RNA-like ER kinase (PERK) activation in TAMs enhances serine biosynthesis by upregulating phosphoserine aminotransferase 1 (PSAT1) and promotes glycolysis through increased glucose transporter 1 (GLUT1) expression, facilitating their immunosuppressive polarization. Deleting IRE1α or PERK in TAMs reprogrammes their phenotype, reducing tumour progression and improving responses to immune checkpoint blockade (ICB). In neutrophils, ER stress activates IRE1α and activating transcription factor 6 (ATF6), reinforcing their pro-tumour phenotype and limiting early T cell responses by upregulating arginase 1 (ARG1) and prostaglandin E2 (PGE₂). Deleting IRE1α in neutrophils delays tumour growth and enhances the efficacy of programmed cell death protein 1 (PD1) blockade in primary high-grade serous ovarian cancer models. ER stress also increases Nectin2 and chemokine ligand 5 (CCL5) expression through transcriptional control, which was found to suppress antitumoural T cell responses. In monocytic-myeloid derived suppressor cells (M-MDSCs), PERK preserves mitochondrial DNA integrity, promoting immunosuppression. Ablation of PERK in MDSCs limits phospho-NRF2 antioxidant activity, therefore increasing the levels of ROS. The increased ROS triggers mitochondrial DNA leakage, activating the stimulator of IFN genes (STING) pathway and enhancing antitumour immunity through type I interferon (IFN-I) secretion. Activation of the PERK–ATF4–C/EBP homologous protein (CHOP) axis also upregulates C/EBPβ expression, which induces IL-6 secretion and downstream signal transducer and activator 3 (STAT3) phosphorylation. Phosphorylated STAT3 directly binds to the Arg1 promoter, inducing its expression and thereby regulating MDSC immunosuppressive function. IRE1α–XBP1s activation supports natural killer (NK) cell proliferation and mitochondrial function by upregulating MYC. This process sustains NK cell-mediated tumour control in mouse melanoma models. UPR dysregulation in tumour-associated myeloid cells therefore contributes to reduced antigen presentation, impaired cytotoxicity against cancer cells, increased T cell suppression and resistance to ICB. b, Tumour-induced ER stress provokes aberrant UPR activation in infiltrating T cells, altering their transcriptional, metabolic and functional profiles, ultimately compromising adaptive immunity. Restricted glucose availability or decreased glucose uptake causes persistent ER stress by limiting N-linked glycosylation of ER-resident proteins. This causes constitutive IRE1α–XBP1s signalling in ovarian cancer-infiltrating CD4⁺ T cells, which dampens glutamine uptake and blunts T cell mitochondrial respiration. In CD8⁺ T cells, cholesterol and tumour-derived factor uptake induces ER stress through IRE1α–XBP1s signalling (as demonstrated in ovarian tumours). This suppress transgelin 2 (TAGLN2), a cytoskeletal element essential for fatty acid-binding protein 5 (FABP5)-mediated lipid uptake and mitochondrial fatty acid oxidation (FAO), thus promoting T cell dysfunction. This also upregulates immune checkpoint molecule expression, including PD1, T cell immunoglobulin and mucin-domain-containing-3 (TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and lymphocyte activation gene 3 (LAG3). Taurine deprivation in intratumoural CD8⁺ T cells activates PERK–ATF4 signalling, also upregulating immune checkpoint molecules, promoting T cell exhaustion. CTLA4, cytotoxic T lymphocyte protein 4; MHC-I, major histocompatibility complex I; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PMN-MDSC, polymorphonuclear myeloid-derived suppressor cell; RIDD, regulated IRE1α-dependent decay.