bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–08–09
thirteen papers selected by
Susan Logue, University of Manitoba
  1. Diabetic and ER-stressed pancreatic islet β cells are in need of some JNK removal.
  2. Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.
  3. An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.
  4. JNK and p53 cause human and mouse β cell death during excessive unfolded protein response.
  5. Bruno 1 remodels P-bodies to protect select mRNAs during the early ER stress response.
  6. The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.
  7. Slc26a9 guards gastric mucosa against portal hypertension by reducing ER stress-induced apoptosis.
  8. RBM39 modulates UPR signaling through alternative splicing of IRE1α/ERN1.
  9. Calreticulin as a stress-responsive integrator of ER proteostasis, calcium homeostasis, and immune clearance.
  10. A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
  11. Inhibition of Acetyl-CoA-carboxylase induces endoplasmic reticulum stress and augments the efficacy of anti-cancer therapies.
  12. XBP1 signaling from tumor metabolic stress to myeloid driven immunotherapy resistance (Review).
  13. Endoplasmic reticulum stress promotes leukemic plasmacytoid dendritic cell differentiation skewing and immune suppression in acute myeloid leukemia.
  1. J Clin Invest. 2026 Aug 03. pii: e209808. [Epub ahead of print]136(15):
    Diabetic and ER-stressed pancreatic islet β cells are in need of some JNK removal.
    Jonathan M Palozzi, Pere Puigserver.
      Pancreatic β cells regulate glucose homeostasis through insulin secretion, but nutrient overload and genetic defects can trigger ER stress and apoptosis, contributing to type 2 diabetes. Within β cells, the kinases PERK, IRE1α, and ATF6 initiate the unfolded protein response (UPR) as a result of ER stress, a process that is constitutively suppressed under nonstress conditions by GRP78 binding to these proteins. To gain insight into the mechanisms of β cell death upon dysregulated ER stress, Sharma et al. used β cell-specific GRP78 knockout models, revealing that hyperactivation of the UPR promoted β cell death primarily through the IRE1α/JNK/p53 signaling pathway. Pharmacological inhibition of JNK improved β cell survival, increased insulin levels, and lowered blood glucose in multiple diabetic mouse models. These findings highlight JNK signaling as a promising therapeutic target for preserving β cell function.
    DOI:  https://doi.org/10.1172/JCI209808
  2. Mol Diagn Ther. 2026 Aug 07.
    Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.
    Mercilena Benjamin, Surender Kumar Sharawat, Anita Chopra.
      Endoplasmic reticulum (ER) is a multifunctional organelle essential for maintaining proteostasis, lipid and carbohydrate metabolism, and calcium homoestasis. Rapidly dividing cancer cells driven by oncogenes, elevated translational output, increased metabolic demands, and a hostile tissue microenvironment overwhelm the protein-folding machinery of ER, leading to massive accumulation of unfolded proteins within the ER's lumen leading to chronic ER stress. This activates the unfolded protein response (UPR), a conserved signaling network mediated by three principal sensors: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1-alpha (IRE1α), and activating transcription factor 6 (ATF6), which functions to restore proteostasis or induce apoptosis under unresolved ER stress. Accumulating evidence indicates that malignant cells hijack the pro-adaptive function of the UPR pathway not only to thrive but also to promote cancer progression by invasion and metastasis. UPR activation modulates transcriptional and translational programs that contribute to angiogenesis, invasion, metastasis, immune escape, and chemoresistance. In this review, we dissect how cells balance this tightrope between adaptation and cell death in the context of cancer. We also explore how UPR signaling drives angiogenesis, metastasis, immune-evasion, and chemoresistance before finally discussing its therapeutic potential.
    DOI:  https://doi.org/10.1007/s40291-026-00869-y
  3. Cell Chem Biol. 2026 Aug 05. pii: S2451-9456(26)00279-5. [Epub ahead of print]
    An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.
    Roza Ogurlu, Eliya B Sanchez, Joshua A Hull, Sophia M Fergione, Vivian Yudistyra, Gabriela M Webb, Helen L Wu, Cleiton T Pessoa, Matthew C Humkey, Sofia K Potter, Alan Rosales, Heather A Vincent, Jonah B Sacha, Aravind Asokan.
      Therapeutic protein overexpression can overwhelm endoplasmic reticulum (ER) folding capacity, trigger unfolded protein response (UPR) signaling, and compromise the safety of gene and mRNA therapies. Here, we engineer stress-responsive RNA rheostats that couple transgene expression to endogenous ER stress sensing. Short RNA elements derived from X-box-binding protein 1 (XBP1) mRNA undergo inositol-requiring enzyme 1α (IRE1α)-dependent splicing under ER stress, inducing a frameshift that attenuates downstream protein expression. XBP1 switches function across DNA and mRNA delivery platforms and regulate the expression of fluorescent reporters, coagulation factor VIII, and Leronlimab, a therapeutic anti-CCR5 monoclonal antibody. Switch activation reduces ER stress markers while preserving expression under homeostatic conditions. We further demonstrate the regulation of Leronlimab expression in vivo using recombinant adeno-associated virus vectors. Together, these findings establish programmable RNA feedback control as a strategy for linking cellular proteostasis to therapeutic protein expression and improving the safety of gene and mRNA therapies.
    Keywords:  ER stress; RNA splicing; RNA switches; endoplasmic reticulum stress; gene therapy; mRNA therapy; protein overexpression; rheostat; unfolded protein response
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.006
  4. J Clin Invest. 2026 Aug 03. pii: e193035. [Epub ahead of print]136(15):
    JNK and p53 cause human and mouse β cell death during excessive unfolded protein response.
    Rohit B Sharma, Christine Darko, Ying Wang, Thalia A Castro, Tara Doma Lama, Brian Gablaski, Andrew Rappa, David Redmond, Jason K Kim, Amy S Lee, Laura C Alonso.
      Endoplasmic reticulum (ER) stress contributes to β cell death in both Type 1 and Type 2 diabetes (T1D and T2D). However, the molecular mechanisms driving β cell death during ER stress remain insufficiently defined, limiting development of protective therapies. GRP78, an ER chaperone, is the master regulator of unfolded protein response (UPR), suppressing UPR initiators during the unstressed state and releasing them to allow UPR activation during stress. To dissect the pathways leading to ER-stress response related β cell decompensation, we engineered mice genetically lacking GRP78 in pancreatic β cells. GRP78 deletion caused acute insulin-deficient diabetes in pups before weaning, with reduced β cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses identified a JNK-p53 axis downstream of IRE1 kinase as a key mediator of β cell death during UPR activation. In vivo JNK inhibition protected against β cell death in 2 distinct ER stress diabetes models. In human β cells, pharmacological inhibition of both JNK and p53 improved β cell survival during GRP78 knockdown-induced UPR. These findings provide insight into mechanisms causing β cell death during ER stress and outline possible therapeutic targets to preserve insulin secretory capacity in diabetes.
    Keywords:  Cell stress; Diabetes; Endocrinology; Insulin; Metabolism
    DOI:  https://doi.org/10.1172/JCI193035
  5. Life Sci Alliance. 2026 Oct;pii: e202603806. [Epub ahead of print]9(10):
    Bruno 1 remodels P-bodies to protect select mRNAs during the early ER stress response.
    Samantha N Milano, Livia V Bayer, Julie J Ko, Gwendolyn S Posner, Albina H Granovsky, Diana P Bratu.
      P-bodies are cytoplasmic membraneless organelles involved in mRNA storage, yet their role in cellular stress responses remains unresolved. Here, we demonstrate that P-bodies are remodeled during the early response to ER stress throughout Drosophila melanogaster oogenesis. Notably, this remodeling occurs within minutes of stress induction and precedes stress granule formation. This early remodeling is characterized by changes in P-body morphology and internal organization and promotes selective mRNA storage. Mechanistically, we find that this process is driven by transcriptional up-regulation of the RNA-binding protein, Bruno 1, downstream of ATF4-dependent stress signaling, thereby establishing a connection between the unfolded protein response and condensate regulation. Consistent with this model, loss of Bruno 1 abolishes, whereas its overexpression enhances, P-body remodeling, demonstrating that stress-induced changes in RNA-binding protein levels can reprogram condensate properties. Together, our findings reveal that P-bodies function as stress-responsive hubs enabling selective preservation of essential mRNAs during ER stress. More broadly, this work uncovers a previously unrecognized mechanism by which stress signaling pathways reorganize cytoplasmic architecture to shape mRNA fate.
    DOI:  https://doi.org/10.26508/lsa.202603806
  6. Biochim Biophys Acta Rev Cancer. 2026 Aug 03. pii: S0304-419X(26)00148-4. [Epub ahead of print] 189676
    The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.
    Guanran Ding, Wang Yang, Yixin Zhao, Xiangliang Liu, Jiuwei Cui.
      Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.
    Keywords:  Arginine; Autophagy; Cancer cachexia; Endoplasmic reticulum stress; IRE1α; Muscle wasting; Therapeutic target; Ubiquitin-proteasome system; XBP1
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189676
  7. Life Sci. 2026 Aug 05. pii: S0024-3205(26)00429-7. [Epub ahead of print] 124620
    Slc26a9 guards gastric mucosa against portal hypertension by reducing ER stress-induced apoptosis.
    Zhiyuan Ma, Zhiqiang Yi, Bei Ji, Chunli Hu, Shuhui Liu, Zhengxing Zhou, Minglin Zhang, Jiaxing Zhu, Guorong Wen, Hai Jin, Jiaxing An, Biguang Tuo, Taolang Li, Xuemei Liu.
       BACKGROUND: Slc26a9 is a member of the Slc26a family that is highly expressed in the stomach and is a key regulator for maintaining gastric mucosal homeostasis. Slc26a9 deletion in mice impairs the gastric mucosal barrier. However, the role of Slc26a9 in PHG has never been investigated.
    METHODS: Slc26a9 expression was analyzed in human PHG and control gastric tissues. A PVL-induced PHG model was established in Slc26a9fl/fl and parietal cell-specific Slc26a9 knockout mice to evaluate mucosal injury, ER stress, and apoptosis. Adenoviral overexpression in vivo and gene silencing in GES-1 cells were used to explore the underlying mechanisms.
    RESULTS: In this study, the Human PHG samples showed both significantly reduced Slc26a9 mRNA and protein expression when compared to healthy controls. Parietal cell-specific Slc26a9 gene deletion aggravates gastric mucosal injury, gastric mucosal epithelial apoptosis, mitochondria apoptotic, and ER stress in PHG. Restoration of Slc26a9 expression in the gastric mucosa of mice using an adenovirus overexpressing Slc26a9 reversed the aggravated endoplasmic reticulum stress, mitochondrial apoptosis, epithelial apoptosis, and gastric mucosal injury caused by Slc26a9 deficiency. In addition, downregulation of Slc26a9 expression induced apoptosis in GES-1 cells by activating the endoplasmic reticulum stress-mitochondrial apoptosis pathway. Mechanistically, Slc26a9 may inhibit endoplasmic reticulum stress by interacting with valosin-containing protein (VCP).
    CONCLUSIONS: Slc26a9 protects the mucosal defense barrier against PHG by attenuating ER stress-mediated mitochondria-dependent apoptotic signaling. Slc26a9 may be a novel therapeutic target for PHG.
    Keywords:  Endoplasmic reticulum stress; Epithelial apoptosis; Mitochondria-dependent apoptosis; Portal hypertensive gastropathy; Slc26a9
    DOI:  https://doi.org/10.1016/j.lfs.2026.124620
  8. Genes Dev. 2026 Aug 07.
    RBM39 modulates UPR signaling through alternative splicing of IRE1α/ERN1.
    Jeongjin J Kim, Amit K Behera, Arun Prasath Damodaran, Shreya Kordale, Thomas Gonatopoulos-Pournatzis.
      The unfolded protein response (UPR) preserves endoplasmic reticulum proteostasis through coordinated signaling pathways, including the IRE1α-XBP1 axis, which promotes adaptive transcriptional programs via noncanonical XBP1 mRNA splicing. However, upstream mechanisms regulating this pathway remain incompletely defined. Here, we apply CRASP-seq, a scalable RNA-coupled CRISPR screening platform, to systematically identify regulators of XBP1 splicing. We uncovered the U2 snRNP auxiliary factor RBM39 as a critical positive regulator of this process. Perturbation of RBM39 or U2 snRNP components induces alternative splicing of ERN1, leading to exon-18 skipping and the production of an unstable transcript subject to nonsense-mediated decay, as well as a truncated IRE1α isoform that acts in a dominant-negative manner to suppress XBP1 splicing. Mechanistically, we show that heat shock reduces RBM39 functional activity and promotes ERN1 exon-18 skipping, thereby attenuating IRE1α-XBP1 signaling. Functionally, hyperactivation of this pathway is detrimental under proteotoxic stress, suggesting that exon-18 skipping serves as a stress-adaptive mechanism to limit UPR output. Together, our findings reveal a previously unrecognized regulatory axis linking the canonical splicing machinery to UPR signaling and establish alternative splicing of ERN1 as a key modulator of cellular stress responses.
    Keywords:  CRASP-seq; ERN1; IRE1α; RBM39; RNA-coupled CRISPR screening; U2 snRNP; XBP1; alternative splicing; pre-mRNA processing; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1101/gad.353632.126
  9. Mol Biol Rep. 2026 Aug 03. pii: 1324. [Epub ahead of print]53(1):
    Calreticulin as a stress-responsive integrator of ER proteostasis, calcium homeostasis, and immune clearance.
    Arsene Mutombo Menga, Xin Hong, Rui Shi.
      Calreticulin (CALR) is a multifunctional endoplasmic reticulum (ER) protein that couples lectin-like chaperone activity in the calnexin/calreticulin cycle with high-capacity Ca²⁺-binding, thereby linking ER proteostasis to luminal calcium homeostasis. Although classically viewed as an ER-resident chaperone, CALR is increasingly recognized as a stress-responsive regulator whose functions extend beyond the ER lumen. Under stress, CALR can relocalize to the cell surface or extracellular space, where it functions as an immune-recognition and pro-clearance signal for damaged or dying cells. Across aging and chronic degenerative conditions, persistent ER stress, altered calcium handling, and defective clearance of stressed or senescent cells may reshape CALR expression, localization, and stress-responsive functions. However, CALR has not been widely conceptualized as an integrative regulator linking ER proteostatic stress, calcium dysregulation, senescence-associated remodeling, and immune surveillance. In this review, we examine CALR as a stress-responsive integrator of ER proteostasis, calcium homeostasis, senescence-associated stress adaptation, and immune-mediated clearance, and discuss how this framework may inform mechanistic studies and therapeutic strategies in chronic degenerative diseases.
    Keywords:  Calcium homeostasis; Calreticulin; Immune clearance; Proteostasis; Senescence
    DOI:  https://doi.org/10.1007/s11033-026-12416-3
  10. Cancer Cell. 2026 Aug 03. pii: S1535-6108(26)00312-0. [Epub ahead of print]
    A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
    Yang Zheng, Caleb Cheng, Yizhi Cao, Gabriel Cruz, Yuping Zhang, Radha Paturu, Somnath Mahapatra, Jing Hu, Rahul Mannan, Hüseyin Karabürk, Rupam Bhattacharyya, Yitong Yin, Yi Zhao, Wenyan Liu, Xuhong Cao, Hui Xue, Chungen Li, Zhen Wang, Stephanie J Miner, Zachery R Reichert, Rohit Mehra, Ulka Vaishampayan, Vaibhav Sahai, Lois S Weisman, Ke Ding, Costas A Lyssiotis, Yuzhuo Wang, Arul M Chinnaiyan, Yuanyuan Qiao.
      Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-adaptive lipid kinase axis that supports adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, exacerbates ER stress, and activates a compensatory sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
    Keywords:  PI(3,5)P(2); PIKfyve; SREBP; autophagy; endoplasmic reticulum stress; fatty acid synthase; lipid metabolism; lysosome; neuroendocrine prostate cancer; unfolded protein response
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.003
  11. Clin Cancer Res. 2026 Aug 03.
    Inhibition of Acetyl-CoA-carboxylase induces endoplasmic reticulum stress and augments the efficacy of anti-cancer therapies.
    Naing Lin Shan, Henriette Balinda, Jiawei Dai, Yueyue Wang, Hao-Kuen Lin, Michal Marczyk, Gerson Espinoza Campos, Sheila Umlauf, Martina S J McDermott, Iriana Colorado, Sabine M Lang, Yulia V Surovtseva, Rena Feinman, Dennis J Slamon, Kim R M Blenman, Qin Yan, Viswanathan Muthusamy, Andrew J Brenner, Lajos Pusztai.
       PURPOSE: Increased dependence on de novo fatty acid synthesis is a key feature of metabolic rewiring in cancer cells. Acetyl-CoA-carboxylase (ACC) is the rate limiting enzyme of de novo fatty acid synthesis. We examined the anti-cancer activity of the ACC inhibitor, PF-05175157, alone and in combination with approved anticancer therapies.
    EXPERIMENTAL DESIGN: PF-05175157 activity was assessed in high throughput cell line screen and in mouse xenograft experiments. Drug-drug interactions were tested with 166 FDA-approved agents. Mechanistic studies included lipid profiling and evaluation of endoplasmic reticulum (ER) stress and unfolded protein response markers and downstream effects on cellular metabolism and viability.
    RESULTS: PF-05175157 showed broad anti-cancer activity including in cells resistant to targeted therapies and inhibited tumor growth in xenograft experiments. Combination studies demonstrated enhanced efficacy with multiple FDA-approved anti-cancer drugs, including tyrosine kinase inhibitors and chemotherapy agents. Lipid profiling showed increase in cholesterol esters and unsaturated long-chain fatty acids that alter membrane fluidity. These changes were associated with evidence of ER stress and unfolded protein response followed by metabolic arrest leading to cell death.
    CONCLUSIONS: ACC inhibition with PF-05175157 has a potential for clinical application as an anti-cancer agent and due to its unique mechanism of action and broad synergy with existing anti-cancer therapies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-26-1028
  12. Int J Mol Med. 2026 Oct;pii: 280. [Epub ahead of print]58(4):
    XBP1 signaling from tumor metabolic stress to myeloid driven immunotherapy resistance (Review).
    Ziwei Chen, Jiaqi Wu, Wenxi Liu, Jie Tan, Xiaochun Peng, Yanhua Zhang, Gai Liang.
      The tumor microenvironment (TME) is a complex ecosystem with harsh conditions, such as hypoxia, nutrient deprivation, metabolic acidosis and oxidative stress, that promote tumor progression and shape immune responses. In this environment, endoplasmic reticulum stress and the unfolded protein response are activated, with the transcription factor X‑box binding protein 1 (XBP1) serving a key role. XBP1 not only maintains cell protein homeostasis, but also modulates the generation, metabolic adaptation and immunosuppressive function of myeloid‑derived suppressor cells (MDSCs). The TME and tumor‑derived factors, such as exosomes, remotely activate XBP1 in MDSCs, enhancing their survival and immunosuppressive capability by reprogramming lipid and glucose metabolism and upregulating the expression of arginase‑1, inducible nitric oxide synthase, reactive oxygen species and immunosuppressive cytokines. The present review aimed to describe the TME stress‑XBP1‑MDSC‑immunosuppression axis, its molecular mechanisms and the role of XBP1 in MDSC heterogeneity and plasticity. Targeting XBP1 may enhance the efficacy of existing therapies, particularly immune checkpoint blockade, by alleviating MDSC‑mediated immunosuppression, offering a novel paradigm for understanding and reversing tumor immune escape.
    Keywords:  X‑box binding protein 1; endoplasmic reticulum stress; myeloid‑derived suppressor cells; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.3892/ijmm.2026.5951
  13. Leukemia. 2026 Aug 03.
    Endoplasmic reticulum stress promotes leukemic plasmacytoid dendritic cell differentiation skewing and immune suppression in acute myeloid leukemia.
    Xingcheng Yang, Juan Peng, Xia Mao, Lei Zhang, Shaolong He, Chunyan Wang, Yicheng Zhang, Yuting Tang, Jue Wang, Jia Wei.
      Mature plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia (pDC-AML) is a distinct entity with poor prognosis. Yet, the mechanisms underlying the immune evasion and aberrant pDC expansion remain poorly understood. We performed multi-omic profiling of 18 pDC-AML cases, along with 207 non-pDC-AML and 16 BPDCN cases as controls. Single-cell RNA-seq and proteomic analyses demonstrated that pDC-AML leukemia stem cells exhibited unfolded protein response activation, particularly the IRE1α-XBP1 axis, which preceded the acquisition of the pDC maturation program. Supporting this, pharmacological induction of endoplasmic reticulum stress in myeloid cells upregulated BCL11A, the master transcription factor in pDC differentiation, and induced a pDC immunophenotype (CD123+BDCA2+). Importantly, pDC-AML-derived pDCs exhibited functional impairment, including compromised antigen-presenting pathways and reduced interactions between pDCs and CD8+ T cells. scTCR-seq analysis revealed significantly restricted T-cell clonal expansion in the pDC-AML bone marrow microenvironment, which correlated with leukemic burden and reversed upon clinical remission. Notably, allogeneic hematopoietic stem cell transplantation (HSCT) significantly improved overall and progression-free survival, abrogating the prognostic disadvantage relative to non-pDC-AML. Collectively, these findings establish impaired anti-leukemia immunity as a hallmark of pDC-AML, support early HSCT as a clinical priority, and identify ER-stressed pDCs as a potential novel therapeutic target.
    DOI:  https://doi.org/10.1038/s41375-026-03080-4
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