The unfolded protein response, or UPR, exists because the endoplasmic reticulum is the cell’s protein-folding factory. When oncogenic stress, oxidative damage or metabolic strain disrupts folding, misfolded proteins pile up in the ER lumen, a condition known as ER stress. Three transmembrane sensors then sound the alarm: IRE1α, PERK and ATF6. IRE1α, a dual kinase and ribonuclease, splices the mRNA of X-box binding protein 1 to produce the transcription factor XBP1s, which ramps up production of chaperones and folding enzymes, while also degrading selected mRNAs through a process called regulated IRE1-dependent decay. PERK phosphorylates the translation initiation factor eIF2α, throttling global protein synthesis to lighten the folding load while permitting translation of ATF4, which steers the cell toward redox balance and metabolic adaptation. ATF6 travels to the Golgi apparatus, where it is cleaved into a cytosolic transcription factor that boosts folding capacity. Together these branches either restore order or, if the damage is beyond repair, push the cell into apoptosis.

What makes the UPR so consequential for cancer immunology is that the same secretory pathway it governs is the one tumours and immune cells use to talk to each other. Death receptors, immune checkpoint ligands such as PD-L1, chemokines and cytokines all depend on ER function for their production and trafficking. The review lays out three arenas in which tumour-intrinsic UPR signalling shapes the immune battlefield: immune recognition of tumour cells, immune-mediated tumour cell killing, and the broader chemical and vesicular communication between tumour and immune cells. In each arena, the evidence points to a system that can be bent toward immune evasion.

Immune recognition begins with antigen presentation. Tumour-derived mutant proteins are chopped by the proteasome into peptides, ferried into the ER by the transporter associated with antigen processing, loaded onto MHC class I molecules with the help of chaperones such as Tapasin, and displayed on the cell surface for scrutiny by CD8-positive cytotoxic T cells. NK cells, by contrast, monitor MHC-I expression itself, becoming activated when it drops or when stress ligands appear. The review details how UPR signalling can sabotage this display at multiple points. In lung and cervical cancer cells, ER stress raises XBP1s, which induces the microRNA miR-346; this microRNA targets TAP1 mRNA and cuts off the peptide supply to the ER. XBP1 inhibition restores surface MHC-I in tongue squamous cell carcinoma by suppressing TPP2, a protease that devours antigenic peptides. IRE1-dependent decay can even degrade the mRNAs encoding MHC-I heavy chains and Tapasin in dendritic cells, limiting T cell activation from the other side of the synapse. PERK contributes too: by attenuating translation through eIF2α phosphorylation, it reduces the pool of peptides available for loading onto MHC-I molecules.

A second recognition route is immunogenic cell death, a form of dying that broadcasts danger signals. When chemotherapy or radiation triggers ER stress, the chaperone calreticulin flips to the cell surface as an ‘eat me’ signal for dendritic cells via the receptor LRP1, while ATP and HMGB1 spill out of the dying cell to activate immune receptors such as P2X7R and TLR4. Here the UPR can work in the immune system’s favour. PERK-eIF2α signalling has emerged as a major driver of calreticulin exposure, apparently through caspase-8-dependent trafficking of the chaperone from the ER to the plasma membrane via the Golgi. In murine melanoma, doxorubicin-induced ER stress promotes calreticulin exposure, and its engagement of the activating receptor NKp46 strengthens the drug’s anti-tumour effect. Intriguingly, the review notes that ICD can also occur when PERK is inhibited in ER-stressed melanoma cells, with dying cells exposing calreticulin and releasing HMGB1 and ATP independently of caspase activation — a reminder that PERK is important but not universally required, and that the rules depend on the type of stress and the tumour involved. Blocking the ER chaperone BiP, which normally holds the three UPR sensors in check, similarly enhances radiation-induced ICD in human glioma stem cells.

Once a tumour cell is recognised, it must still be killed, and here the UPR again tilts the scales. PD-L1, the co-inhibitory ligand that engages PD-1 on T cells and drives their exhaustion, is upregulated by ER stressors such as thapsigargin or the BiP inhibitor HA15 through IRE1α’s RNase activity, and BiP appears to stabilise PD-L1 protein directly in triple-negative breast, head and neck and pancreatic cancer cell lines. Strikingly, combining HA15 with anti-PD-1 therapy boosts CD8-positive T cell infiltration and cytotoxicity in murine melanoma, showing that UPR-driven checkpoint modulation can be therapeutically exploited. NK cell attack is blunted through a parallel route: IRE1α-XBP1s signalling represses the stress ligand MICA in melanoma cells by inhibiting the transcription factor E2F1, while ER stress lowers MICA/B post-transcriptionally in hepatocellular carcinoma, and PERK-eIF2α-ATF4 signalling regulates additional NK-activating ligands including ULBP1 and B7-H6. Even the extrinsic death receptor pathway is under UPR control, with XBP1s promoting CD95 expression while RIDD suppresses it, and PERK knockdown independently altering CD95 protein levels.

Beyond direct contact, tumour cells flood their surroundings with soluble signals and extracellular vesicles, and the UPR shapes both. ER stress in prostate cancer, melanoma and lung carcinoma cells promotes release of IL-6, IL-23 and TNF-α, which polarise macrophages toward a pro-inflammatory phenotype via TLR4 while simultaneously impairing dendritic cell cross-presentation and CD8-positive T cell activation. By contrast, HA15-induced ER stress in melanoma enhances secretion of the chemokines CXCL9-11 along with IL-6 and TNF-α, drawing cytotoxic T cells into the tumour — an example of the UPR’s double-edged nature. In triple-negative breast cancer and glioblastoma, IRE1α activity remodels the secretome and myeloid cell recruitment, while loss of tumour IRE1α in lung cancer increases dendritic cell infiltration partly by reducing the immunosuppressive lipid prostaglandin E2. Exosomes add another layer: PERK and IRE1α regulate multivesicular body formation, ATF4 limits lysosomal acidification by inhibiting vesicular-ATPase assembly, and ER stress boosts release of exosomes carrying PD-L1 or miR-27a-3p, which push macrophages toward pro-tumourigenic, PD-L1-high states.

The immune cells themselves are not passive bystanders. Tumour-derived factors activate PERK-ATF4 signalling in macrophages within glioblastoma, driving GLUT1 expression, glucose uptake and lactate production that support an immunosuppressive phenotype; in melanoma, the same pathway promotes serine biosynthesis and lipid oxidation through ATF4-PSAT1. PERK also governs myeloid-derived suppressor cell function through NRF2, and its loss triggers mitochondrial dysfunction and STING-dependent immune activation that reinvigorates CD8-positive T cell responses. Pharmacologically, the IRE1α kinase inhibitor Compound 18 reduced tumour-associated fibroblasts and myeloid-derived suppressor cells in breast tumour xenografts, while the RNase inhibitor MKC8866 — now in Phase 2 clinical trials as ORIN1001 — synergised with docetaxel and with anti-PD-1 therapy to increase T cell and NK infiltration in mouse models. PERK deletion in melanoma cells shrank tumours only in mice with functional T cells, underscoring the immune dependence of the effect, and the PERK inhibitor HC-5404 is being evaluated in a Phase 1 trial across multiple solid tumours.

The review’s central message is that UPR signalling is neither friend nor foe to anti-tumour immunity but a context-dependent dial. Acute ER stress can render tumours more immunogenic and vulnerable, whereas chronic stress fosters adaptation and immune suppression, with the outcome shaped by which branch is engaged, the intensity and duration of stress, tumour lineage and the surrounding immune landscape. The authors highlight the tantalising possibility that IRE1α inhibition can convert immunologically cold tumours into hot ones, restoring sensitivity to checkpoint inhibitors, as seen when docetaxel and MKC8866 were combined in triple-negative breast cancer models. Yet because the UPR is essential for the survival and function of secretory immune cells, the therapeutic window may be narrow, demanding careful target selection, dosing and combination strategies. Open questions abound — whether UPR modulation can enhance CAR-T and CAR-NK cell therapies, and which tumour types with high basal UPR activity stand to benefit most — but the answer to the last may already be taking shape: tumours with pre-existing immune infiltration, where the conversation between cancer and immunity is still alive enough to be redirected.

Subject of Research: The role of the unfolded protein response in regulating tumour-immune cell communication in the tumour microenvironment

Article Title: The Unfolded Protein Response as a Modulator of Cancer‐Immune Cell Communication in the Tumour Microenvironment

Article References: Chee, Y. H., Moncan, M., Reidy, E., Gorman, A. M., & Samali, A. (2026). The Unfolded Protein Response as a Modulator of Cancer‐Immune Cell Communication in the Tumour Microenvironment. Journal of Cellular and Molecular Medicine, 30(19), Article e71380. https://doi.org/10.1111/jcmm.71380

Image Credits: AI Generated

DOI: 10.1111/jcmm.71380

Keywords: unfolded protein response, ER stress, tumour microenvironment, cancer immunotherapy, IRE1α, PERK, PD-L1, antigen presentation, immunogenic cell death, NK cells, T cells, exosomes

The stakes could hardly be higher. According to the review, led by Olabisi Tajudeen Obafemi of the University of South Africa and colleagues, the global number of people living with diabetes surged from 200 million in 1990 to 830 million in 2022. Type 2 diabetes accounts for roughly 90 to 95 percent of those cases and is defined by insulin resistance paired with an insufficient compensatory surge of insulin. Persistent high blood glucose progressively damages the vascular, renal, neurological, ocular and cardiovascular systems, generating enormous morbidity and healthcare expenditure. Current drugs, including sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, mostly manage glucose downstream of the underlying cellular damage.

The authors contend that upstream stress-response pathways deserve far more therapeutic attention because they lie closer to the molecular origins of the disease. Among these, the IRE1α/XBP1 arm of the UPR is the most evolutionarily conserved, meaning that findings in model organisms often translate more readily to human biology. IRE1α is a transmembrane protein with a stress-sensing domain inside the ER lumen and kinase plus endoribonuclease (RNase) domains facing the cytoplasm. Under resting conditions, the chaperone GRP78, also known as BiP, keeps IRE1α inactive. When misfolded proteins accumulate, GRP78 detaches to handle them, allowing IRE1α to oligomerize and trans-autophosphorylate, thereby switching on its RNase domain.

That RNase activity performs one of the most remarkable feats in molecular biology: the unconventional splicing of X-box binding protein 1 (XBP1) mRNA. IRE1α excises a 26-nucleotide intron from XBP1 mRNA in the cytoplasm, producing a frameshift that generates the spliced transcription factor XBP1s. Once in the nucleus, XBP1s switches on genes for ER-associated protein folding, quality control, ER expansion, lipid biosynthesis and enhanced secretory capacity. In its adaptive mode, the pathway is a lifeline, expanding the cell’s folding factory to meet demand. But when ER stress becomes chronic, the same machinery turns destructive, engaging regulated IRE1-dependent decay (RIDD), which degrades essential transcripts, and recruiting inflammatory stress kinases.

The review details how this dual personality plays out across metabolically active tissues. In the liver, XBP1s suppresses gluconeogenesis by promoting the degradation of the transcription factor FOXO1, improving glucose tolerance, while fasting signals phosphorylate hepatic IRE1α at serine 724 to enhance gluconeogenic genes independently of XBP1s. In adipose tissue, XBP1s maintains adipocyte differentiation through the C/EBP family of transcription factors. In pancreatic beta cells, glucose-induced XBP1 splicing expands the machinery needed for proinsulin folding and secretion while limiting oxidative stress; beta-cell-specific XBP1 deficiency reduces insulin granules and weakens glucose-stimulated insulin secretion. Even skeletal muscle uses the pathway adaptively after injury to support regeneration.

Trouble begins when glucotoxicity and lipotoxicity sustain IRE1α signaling beyond its adaptive window. Chronic hyperglycemia hyperactivates IRE1α in beta cells, suppressing insulin gene expression and degrading insulin mRNA through RIDD, converting a protective response into secretory failure. Meanwhile, IRE1α recruits the adaptor protein TRAF2 and activates c-Jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate-1 on inhibitory serine residues. This blocks downstream PI3K/AKT signaling, reduces GLUT4-mediated glucose uptake and drives systemic insulin resistance. In skeletal muscle, XBP1 and ATF6 upregulate the phosphatase SKIP, further attenuating insulin-stimulated glucose uptake. The result is a feed-forward loop: excess nutrients fuel ER stress, stress kinases blunt insulin action, insulin resistance increases beta-cell workload, and the extra biosynthetic burden deepens ER stress.

The inflammatory consequences may be the most striking. The review describes how hyperactivated IRE1α lowers levels of microRNA-17, which normally represses thioredoxin-interacting protein (TXNIP). Stabilized TXNIP mRNA then promotes activation of the NLRP3 inflammasome, triggering caspase-1-mediated maturation of the inflammatory cytokines IL-1β and IL-18. IRE1α/TRAF2 signaling also activates NF-κB, elevating TNF-α, IL-6 and IL-1β and sustaining the low-grade metabolic inflammation that characterizes obesity and T2DM. The pathway even intersects oxidative stress signaling: acute oxidative stress induces IRE1α sulfenylation and activates an IRE1α–p38–NRF2 antioxidant axis, while in diabetic nephropathy a persistent XBP1–HRD1 axis ubiquitinates NRF2 and strips away renal antioxidant protection.

What elevates the review beyond mechanism is its synthesis of preclinical pharmacology on both sides of the pathway. On the activation side, the small molecule IXA4 selectively boosted adaptive IRE1/XBP1s signaling in diet-induced obese mice, reprogramming the hepatic transcriptome to reduce glucose production and steatosis without triggering RIDD. A successor compound, IXA62, extended activity to kidney and lung and increased glucose-stimulated insulin release. Modest hepatic XBP1s overexpression improved hyperglycemia in insulin-resistant mice partly through FOXO1 degradation, and p38-mediated enhancement of XBP1s activity restored euglycemia in severely obese diabetic mice. In adipose tissue, XBP1s overexpression promoted high-molecular-weight adiponectin multimerization and improved insulin sensitivity in lean and ob/ob mice.

On the inhibition side, kinase-inhibiting RNase attenuators (KIRAs) dampen the maladaptive outputs of IRE1α. In mice lacking Bax inhibitor-1, an endogenous negative regulator of IRE1α, excessive RNase activity drove NLRP3 inflammasome activation, beta-cell death and hyperglycemia; the RNase inhibitor STF-083010 reversed beta-cell failure and normalized the metabolic phenotype, and in obese mice it improved glucose tolerance while suppressing inflammatory adipose-tissue macrophages. More recently, KIRA8 restored sphingosine-1-phosphate lyase activity, improved AKT phosphorylation and glucose uptake in muscle cells, and ameliorated glucose metabolism in high-fat-diet-fed animals. Even a pomegranate flower polyphenol extract showed antidiabetic effects linked to inhibition of the hepatic IRE1α–XBP1–CHOP stress axis.

The authors are careful to stress that the pathway’s intrinsic bidirectionality creates a narrow therapeutic window: success will demand tissue-, dose-, duration- and output-selective modulation rather than blanket activation or suppression. Key unanswered questions include the stage-specific thresholds separating adaptive from harmful signaling, head-to-head comparisons of XBP1s activators, RNase inhibitors and kinase-domain modulators in the same models, and how well animal findings extrapolate to human disease. Still, the strategic position of IRE1α/XBP1 at the intersection of ER proteostasis, insulin signaling, inflammation, oxidative stress and beta-cell survival makes it, in the reviewers’ assessment, a credible next-generation target, one that could intervene where diabetes begins rather than merely where its symptoms end.

Subject of Research: The role of the IRE1α/XBP1 unfolded protein response pathway in type 2 diabetes and its potential as a therapeutic target

Article Title: Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity

Article References: Obafemi, O. T., Ayeleso, A. O., Ekundayo, B. E., Obafemi, B. A., Adewale, O. B., Lebelo, S. L., & Ntwasa, M. (2026). Targeting the IRE1α/XBP1 pathway in type 2 diabetes mellitus: from ER stress signaling to therapeutic opportunity. Molecular Biology Reports, 53(1), Article 1688. https://doi.org/10.1007/s11033-026-12876-7

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12876-7

Keywords: IRE1α, XBP1, unfolded protein response, endoplasmic reticulum stress, type 2 diabetes, insulin resistance, pancreatic beta cells, JNK signaling, NLRP3 inflammasome, RIDD, drug targets, metabolic disease

The researchers began with a straightforward hypothesis grounded in clinical observation. Solar lentigines are characterized by persistent basal hyperpigmentation, meaning that the deepest layer of the epidermis remains loaded with melanin long after the original sun exposure that triggered it. They proposed that a sustained stress response centered on IRE1α, a sensor protein embedded in the endoplasmic reticulum membrane, could act on both sides of the pigment equation at once. IRE1α is best known as a key initiator of the unfolded protein response, a cellular quality-control program that activates when misfolded proteins accumulate. When the stress is brief, the response is protective; when it becomes chronic, it can push cells toward senescence, a state of permanent growth arrest.

To test the idea, the team combined human tissue analysis with mechanistic experiments in cell culture. They examined paired samples of lesional and non-lesional skin from patients with solar lentigines, work approved by the Institutional Review Board of Severance Hospital, and complemented the histology with two laboratory models: MNT-1 melanocytes, the pigment-producing cells of the skin, and HaCaT keratinocytes, the cells that form the bulk of the epidermis and normally receive and degrade transferred melanosomes. Crucially, the keratinocyte model included a doxycycline-inducible system as well as constitutive IRE1α expression, allowing the researchers to switch the stress pathway on at will and observe the consequences in a controlled manner.

The tissue findings set the stage. In lesional epidermis, the investigators observed dense accumulations of stage-IV melanosomes, the fully mature, heavily pigmented organelles that melanocytes manufacture and hand off to keratinocytes. Alongside this pigment load, the stressed skin showed elevated levels of IRE1α and p16, a canonical marker of cellular senescence. This co-occurrence was the first hint that the two phenomena, aging-like growth arrest and pigment retention, might share a common driver rather than being parallel but independent consequences of sun damage.

Experiments in the cell models then dissected the mechanism in detail. When the researchers sustained IRE1α signaling, cell proliferation dropped and the senescence markers p16 and p21 rose, confirming that chronic endoplasmic reticulum stress is sufficient to push these epidermal cells into a senescent state. In the melanocytes, the consequences for pigmentation were direct and measurable: IRE1α activation increased tyrosinase activity, the rate-limiting enzymatic step of melanin synthesis, and raised total melanin content. The cells also produced more melanosomes, and those melanosomes were larger than normal, expanding the raw supply of pigment available for transfer to surrounding keratinocytes.

The second half of the dual-hit mechanism emerged from the keratinocyte experiments. Keratinocytes are not passive pigment containers; they are supposed to degrade the melanosomes they receive through lysosomal pathways, a process sometimes described as melanophagy. Under sustained IRE1α signaling, that degradation slowed markedly. The researchers quantified intracellular melanosomes and found they accumulated because they were being broken down more slowly, not because more were arriving. Probing the lysosomal system, they detected diminished LysoTracker signal, indicating reduced lysosomal acidity, along with reduced maturation of cathepsin-B, a key degradative enzyme that requires an acidic environment to become fully active. Autophagic flux, measured with a mRFP–GFP–LC3 reporter that distinguishes early autophagosomes from mature autolysosomes, was also compromised, with fewer autolysosomes forming.

Together, these results sketch a coherent pathological circuit. Chronic IRE1α signaling in melanocytes ramps up melanogenesis, flooding the epidermis with pigment, while the same stress pathway in keratinocytes weakens the lysosomal machinery responsible for clearing that pigment away. The senescent state that accompanies the stress response likely stabilizes the situation, since senescent cells persist in tissue rather than being replaced, maintaining the altered signaling environment over time. The net effect is that pigment is produced faster and cleared more slowly, exactly the combination needed to explain the dense, persistent basal hyperpigmentation that defines solar lentigines.

The study also points toward intervention. The researchers tested two agents: verapamil, a calcium channel blocker better known as a cardiovascular drug, and STF083010, a selective inhibitor of the IRE1α RNase domain, the enzymatic activity through which IRE1α transmits its stress signal. Both compounds lessened melanosome accumulation in the keratinocyte model and partially restored degradative function. While the restoration was partial, the finding is significant because it demonstrates that the pigment-retention phenotype is not irreversible and that the IRE1α–lysosome axis is a plausible therapeutic target. Existing treatments for solar lentigines, such as laser therapy and topical depigmenting agents, aim primarily at melanin production or destruction; a strategy that instead restores the clearance machinery would represent a fundamentally different approach.

The broader implications extend beyond cosmetically visible age spots. The unfolded protein response has been implicated in a wide range of age-related tissue changes, and this study adds a vivid example of how a single stress sensor can couple senescence to a tissue-specific functional outcome, in this case pigmentation. The work also highlights melanophagy as an underappreciated control point in skin color biology. Most research on hyperpigmentation has focused on melanocytes and their synthetic output, but the fate of melanosomes after transfer is equally decisive, and lysosomal acidification and cathepsin maturation emerge from this study as actionable levers. If the findings hold up in further clinical studies, modulating IRE1α activity or supporting lysosomal function could inform the development of treatments not only for solar lentigines but potentially for other disorders of pigment retention.

The research, funded by the National Research Foundation of Korea, Yonsei University College of Medicine and the Korea Health Technology R&D Project, was published as an open-access article and is citable under DOI 10.1007/s00018-026-06389-6. Its central message is elegant in its economy: one stress pathway, acting chronically, produces pigment faster and disposes of it more slowly, while locking the affected cells into senescence. For the millions of people who develop these stubborn brown patches, the study offers something more concrete than a new description of the problem, namely a defined molecular axis that can, at least in laboratory models, be pharmacologically nudged back toward balance. Translating that laboratory result into safe and effective clinical therapy will require further work, but the identification of the IRE1α and lysosome axis as a coupled driver of senescence and pigment retention gives the field a clear and testable direction.

Subject of Research: Chronic endoplasmic reticulum stress linking cellular senescence to persistent skin hyperpigmentation in solar lentigines

Article Title: Chronic ER stress couples cellular senescence with pigment retention

Article References: Hwang, S., Kim, J. Y., Lee, E. J., Oh, D., Bae, Y. J., Kwon, I. J., Park, S., Seo, H. R., Alqahtani, J., Lee, J., & Oh, S. H. (2026). Chronic ER stress couples cellular senescence with pigment retention. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06389-6

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06389-6

Keywords: solar lentigo, IRE1α, unfolded protein response, ER stress, cellular senescence, melanophagy, melanogenesis, lysosomal acidification, keratinocytes, melanocytes, p16, skin aging