bims-scepro 2026-04-26 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–04–26
27 papers selected by
William Grey, University of York

Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis.
Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia.
Imputing causality and clonal dynamics from single-cell transcriptomics in paroxysmal nocturnal hemoglobinuria.
Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour.
IFNγ Drives Long-Term Bone Marrow Niche Dysfunction Following Doxorubicin-Based Chemotherapy.
Synthetic Cell-Based Artificial Stem Cell Niches for Hematopoietic Stem Cell Differentiation.
HDAC8 inhibition targets STAT3-MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia.
Uncovering a role for METTL13 in malignant transformation of human hematopoietic stem cells and in the progression of pediatric leukemia.
MMRN1-EGFR drives sialylglycan-Siglec immune evasion in AML leukemia stem cells.
Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.
Stem11 score: towards rapid clinical prognostication for acute myeloid leukemia.
A comprehensive analysis of humanized mouse models for the study of cancer immunotherapies.
Advancing Hematopoietic Stem Cell Research: The Impact of Bioengineered 3D Bone Marrow Niches.
Proteolytic control of mitochondrial protein translocases.
Monocyte-mediated metabolic rewiring via CD31-CD38 interactions promotes growth and drug-resistance in multiple myeloma.
Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.
Bedaquiline amplifies proteasome inhibitor efficacy and overcomes resistance in multiple myeloma.
Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.
Myosin forces remodel F-actin for mechanosensitive protein recognition.
Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.
Single cell transcriptional evolution of myeloid leukemia of Down syndrome.
A 15-layer multi-omics analysis of gastric cancer ecotypes provides therapeutic insights.
Full-DIA enables complete single-cell proteomics from diaPASEF using deep learning.
Visualizing Newly Synthesized Proteins and Their Degradation Dynamics by Using Long-Wavelength-Emitting Fluorescent Dye-DBCO Conjugates.
Surfaceome Capture by Multiplex biotinylation (SUCAM) enables enhanced identification of cell surface proteins by mass spectrometry.
Salicylic acid modulates its catabolic enzymes via proteasomal degradation linked to SCF-associated proximity networks.
The sleeping threat: targeting cancer dormancy to transform metastasis therapy.

J Clin Invest. 2026 Apr 23. pii: e199690. [Epub ahead of print]

Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis.

Shujing Zhang, Jingjing Liu, Yuan Li, Yi Wang, Lingling Wang, Miaomiao Xu, Yanxia Li, Ge Dong, Shanshan Wang, Yanmei Li, Zhigang Cai, Baobing Zhao.

  Typ515 (W515) mutations in the protein MPL are one of key driver mutations promoting BCR/ABL-negative myeloproliferative neoplasms (MPNs), but their effects on hematopoietic stem cells (HSCs) and MPN-related hematological abnormalities have not been studied in physiological contexts. Here, we established a MplW514L knock-in mouse model which largely mimics human MPLW515L mutation during hematopoiesis. The mutant mice developed an essential thrombocythemia (ET)-like MPN phenotypes, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically we observed that MplW514L-conditioned HSC compartment had a unique disease-initiating capacity however it did not exhibit a obvious advantage of competitive repopulation over wild-type control. Notably, single-cell analysis and flow cytometry profiles support that MplW514L expression led to a significant expansion of megakaryocyte-biased stem cell fate within the HSC pool. Finally, JAK2 inhibitor treatment phenotypically alleviated the ET signs but failed to eliminate the disease-initiating HSCs. These findings underscore the etiology of physiological expression of MPLW515L mutation in HSCs, and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.

Keywords:  Hematology; Hematopoietic stem cells; Leukemias; Mouse models; Oncology

DOI:  https://doi.org/10.1172/JCI199690
Signal Transduct Target Ther. 2026 Apr 21. pii: 145. [Epub ahead of print]11(1):

Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia.

Fanny Gonzales, Pauline Peyrouze, Djohana Laurent, Thomas Boyer, Nihad Boukrout, Cyril Couturier, Soizic Houdiard, Véronique Lisi, Adeline Barthélémy, François Sevrin, Adriana Plesa, Antonino Bongiovanni, Nicolas Pottier, Claude Preudhomme, Vincent-Philippe Lavallée, Konstantinos Geles, Nicolas Duployez, Céline Berthon, Christophe Roumier, Meyling Cheok.

Relapse remains the leading cause of mortality in acute myeloid leukemia (AML), largely due to the persistence of therapy-resistant leukemia stem cells (LSCs). However, surface determinants that sustain LSC function and disease aggressiveness remain incompletely defined. Here, we identify the tetraspanin CD81 as a regulator of LSC function, progression and treatment resistance in AML. Analysis of retrospective patient cohorts revealed that high CD81 surface expression is associated with relapse and adverse clinical outcomes in non-core-binding factor AML. Functional studies demonstrated that elevated CD81 expression promotes chemoresistance and enhances leukemic engraftment in immunodeficient mouse models. In vivo gain- and loss-of-function approaches further established that CD81 drives increased leukemia burden and aggressive disease behavior. Notably, CD81 was enriched within LSC-containing subpopulations, where its expression supported LSC maintenance and resistance to chemotherapy. Mechanistically, CD81 promotes chemoresistance and leukemic aggressiveness through pathways linked to LAPTM4B-mediated STAT3 signaling and enhanced adhesion-dependent cellular interactions. These effects were accompanied by increased migration, invasion, and formation of filopodia-like membrane protrusions. Importantly, therapeutic immunotargeting of CD81 significantly reduced leukemic burden while exhibiting a manageable toxicity profile in preclinical models. Collectively, these findings establish CD81 as a clinically relevant surface marker associated with AML relapse and identify CD81-dependent signaling as a therapeutic vulnerability for targeting LSCs and preventing disease recurrence.

DOI: https://doi.org/10.1038/s41392-026-02697-2
Leukemia. 2026 Apr 22.

Imputing causality and clonal dynamics from single-cell transcriptomics in paroxysmal nocturnal hemoglobinuria.

Hiroki Mizumaki, Shouguo Gao, Zhijie Wu, Fernanda Gutierrez-Rodrigues, Lemlem Alemu, Diego Quinones Raffo, Ivana Darden, Olga Rios, Jennifer Lotter, Sachiko Kajigaya, Jibran Durrani, Emma M Groarke, Bhavisha A Patel, Neal S Young.

Paroxysmal nocturnal hemoglobinuria (PNH) originates from hematopoietic stem cells (HSCs) harboring somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene. Clonal expansion of PIGA-mutated cells occurs uniquely in the setting of bone marrow (BM) failure, but specific pathophysiologic mechanisms remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of BM cells from patients with large (> 50%) and small (10-50%) PNH cell fractions. In patients with large PNH cell fractions, phenotypically normal hematopoietic stem and progenitor cells (HSPCs) upregulated immune response and apoptosis pathways and downregulated cell-cycling pathways compared with PNH-type HSPCs. BM effector cells upregulated immune response pathways, and cell-cell communication between effector cells and normal HSPCs was greater than in controls. In contrast, in patients with small PNH cell fractions, transcriptional changes in normal HSPCs were reversed: downregulation of immune response pathways and upregulation of the cell-cycling pathways. Notably, transcriptional differences associated with PNH cell fractions were primarily in normal HSCs, whereas PNH-type HSCs showed similar transcriptional profiles between patients with large and small PNH cell fractions. These results implicate immunological negative selection against normal HSCs in PNH. Error-corrected DNA sequencing of patients' blood samples identified multiple PIGA mutations in each patient, consistent with strong selection for the resulting phenotype.

DOI: https://doi.org/10.1038/s41375-026-02914-5
Nat Cell Biol. 2026 Apr 24.

Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour.

Chen Wang, Yi Pan, Ruochen Dong, Wenxuan Zhou, Xiaduo Meng, Xi Kang, Ravi Nistala, Richard D Hammer, Linheng Li, XunLei Kang.

Leukaemic stem cells (LSCs) reside in protective bone marrow (BM) niches that promote therapeutic resistance and relapse. Here we characterized longitudinal BM niches supporting LSC survival, distinguishing the metaphysis from the central marrow. Quiescent LSCs preferentially localized to the metaphysis and exhibited reduced stemness and aggressiveness upon mobilization to the central marrow. Targeting DPP4 in acute myeloid leukaemia (AML) cells altered CXCL12 gradients at three spatial scales. Systemically, reversal of the BM-peripheral blood CXCL12 gradient confined AML cells within the BM. At the BM level, disruption of the metaphysis-central marrow gradient displaced LSCs from their protective niche. At the microscale, loss of the CXCL12 gradient between N-cadherin+ stromal cells and the surrounding matrix impaired LSC recruitment. These effects arise from the CXCL12-DPP4-GPC3 axis, in which DPP4 truncates and inactivates CXCL12, whereas stromal GPC3 restrains DPP4 activity. Modulating this axis disrupts niche protection and enhances therapeutic vulnerability in AML.

DOI: https://doi.org/10.1038/s41556-026-01939-3
Blood. 2026 Apr 20. pii: blood.2025030946. [Epub ahead of print]

IFNγ Drives Long-Term Bone Marrow Niche Dysfunction Following Doxorubicin-Based Chemotherapy.

Ximing Li, Alicia G Aguilar-Navarro, Mursal Nader, Soheil Jahangiri, Ho Seok Lee, Gibran Edun, Mark Gower, Dustin Yang, Minerva Fernandez, Brian Lin, Donghun Oh, Stephanie Farhat, David-Michael Phillips, Samantha Bartman, David Iain Murray, Christina Marie Kaszuba, Pathum Kossinna, Manjula Kamath, Cari Whyne, Gregory Schwartz, Jeevisha Bajaj, Thomas Kislinger, Bo O Zhou, Daniel L Coutu, Margarete K Akens, Adele Changoor, Thierry Mallevaey, Federico Gaiti, Courtney L Jones, Shruti Naik, Mark D Minden, Andrea Arruda, Johann K Hitzler, Ki Jun Lee, Yong-Mi Kim, Ralf H Adams, Kishor K Sivaraj, Anastasia N Tikhonova.

Cancer survivors experience long-term skeletal and hematopoietic complications that limit quality of life following chemotherapy (CTX), yet the mechanisms underlying these defects remain incompletely understood. Using a murine model of doxorubicin (DOX)-based leukemia induction therapy, we show that CTX induces inflammatory remodeling of the bone marrow (BM) niche. DOX treatment resulted in loss of arteriolar vasculature, blockade of mesenchymal stromal cell (MSC) differentiation, trabecular bone loss, and reduced niche capacity to maintain hematopoietic stem cells (HSCs). These defects were accompanied by aberrant immune activation within the BM, marked by increased interferon-γ (IFNγ) production by CD8⁺ T cells. Inhibition of IFNγ signaling partially restored arteriolar vessels and adipogenic differentiation. Moreover, combined IFNγ blockade and deferoxamine mesylate (DFM), which promotes vascular recovery, attenuated chemotherapy-associated skeletal damage. Consistent with these findings, paired BM samples collected at diagnosis and post-CTX from leukemia patients exhibited altered MSC lineage priming, upregulation of inflammatory pathways, and expansion of BM CD8⁺ memory T cells after treatment. Together, these findings implicate IFNγ-driven chronic inflammatory remodeling as a central mechanism of CTX-associated BM niche dysfunction and pinpoints inflammatory signaling as a potential target to preserve BM function and long-term tissue integrity.

DOI: https://doi.org/10.1182/blood.2025030946
Chembiochem. 2026 Apr 28. 27(8): e202500864

Synthetic Cell-Based Artificial Stem Cell Niches for Hematopoietic Stem Cell Differentiation.

Ivaylo Balabanov, Sara Madureira, Anna Burgstaller, Maja Fehlberg, Nils Piernitzki, Nurzhan Abdukarimov, Franziska Lautenschläger, Oskar Staufer.

  Hematopoietic stem cells (HSCs) receive a combination of biochemical and biomechanical signals within the bone marrow that guide their differentiation process. These include soluble factor signaling with cytokines, cellular confinement in the stem cell niche, and contact-dependent receptor-ligand interactions with stromal cells. Recreating this complex microenvironment in vitro is a principal engineering challenge for regenerative therapies and tissue engineering. While cytokines can be easily supplemented in vitro, and several systems for confined HSC culture have been developed, integrating receptor-based intercellular interactions found in stem cell niches has only been achieved with quantitatively undefined heterotypic co-cultures. We report here the development of microwell-based systems that integrate synthetic cells to mimic receptor-ligand interactions within hematopoietic niches. The synthetic cells are based on droplet-supported lipid bilayers (dsLBs) with cytomimetic stiffness and present Notch receptor ligands on a laterally mobile lipid membrane. We show the system's applicability to individually tune the three signaling axes: soluble factors, confinement, and intercellular interactions for HSC differentiation. Introducing synthetic cells as an alternative to coculture and feeder cells opens the possibility to engineer precisely defined HSC niches with adjustable biochemical and biomechanical properties.

Keywords:  artificial cells; confinement; microwells; synthetic microenvironments; synthetic tissue

DOI:  https://doi.org/10.1002/cbic.202500864
Leukemia. 2026 Apr 21.

HDAC8 inhibition targets STAT3-MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia.

Lianjun Zhang, Wancheng Guo, Yu-Hsuan Fu, Dijiong Wu, Man Li, Ying-Chieh Chen, Chi-Yang Tseng, Wei-Kai Hua, Le Xuan Truong Nguyen, Xin He, Haojie Dong, Lei Zhang, Bin Zhang, Ling Li, Guido Marcucci, Ya-Huei Kuo.

KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is an aggressive AML subtype characterized by 11q23 chromosomal rearrangements involving KMT2A gene and clinically associated with poor prognosis. Herein, we show that HDAC8 is upregulated in KMT2A-r AML and high HDAC8 is associated with poor overall survival in KMT2A-r AML patients. Using a KMT2A::MLLT3 mouse model, we demonstrate that both genetic knockout and pharmacological inhibition of HDAC8 significantly delayed leukemia progression, prolonged survival and reduced disease recurrence. Mechanistically, HDAC8 inhibition downregulates STAT3-MYC axis independent of TP53 status across AML genetic subtypes. Biochemical assays revealed that HDAC8 binds directly to STAT3, promoting its deacetylation and stabilization, while HDAC8-selective inhibitor (HDAC8i) treatment results in increased STAT3 acetylation and subsequent STAT3 degradation which in turn downregulates MYC. Given that STAT3-MYC signaling promotes cell survival and Venetoclax resistance, we show that HDAC8i exhibits synergistic anti-leukemia activity with Venetoclax in primary AML cells regardless of TP53 status. Combination of HDAC8i and Venetoclax synergistically reduced leukemia burden and significantly prolonged survival in both KMT2A::MLLT3 AML and patient-derived xenograft models. This study highlights the regulatory function of HDAC8 on STAT3-MYC and provides the proof-of-principle for targeting HDAC8 in combination with Venetoclax for the treatment of KMT2A-r AML.

DOI: https://doi.org/10.1038/s41375-026-02950-1
Cell Death Dis. 2026 Apr 25.

Uncovering a role for METTL13 in malignant transformation of human hematopoietic stem cells and in the progression of pediatric leukemia.

Sabina Enlund, Chae-Eun Lim, Isabella Hoang, Sonali Joshi, Maria Rivera, Adena Pepich, Amanda Ramilo Amor, Jacob Short, Cecilia Thomsson, Indranil Sinha, Shahrzad Shirazi Fard, Anna Nilsson, Ola Hermanson, Qingfei Jiang, Frida Holm.

Post-transcriptional RNA modifications, such as N6-methyladenosine (m6A) methylation and adenosine to inosine (A-to-I) editing, are critical regulators of hematopoietic stem cell (HSC) self-renewal and differentiation, yet their precise contributions to malignant transformation are not fully elucidated. In this study, we uncovered the epitranscriptomic landscape caused by knockdown of genes from the methyltransferase (METTL)-family in hematopoietic stem and progenitor cells (HSPCs). We identified both converging and distinct effects of METTL3 and METTL14, known members of the m6A writer complex, as well as orphan gene METTL13. Amongst METTL-family members, only METTL13 transcription was increased following adenosine deaminase acting on RNA 1 (ADAR1) overexpression in HSPCs. This transcriptional pattern suggests that METTL13 may participate in biological programs that partially overlap with those controlled by the m6A writer complex and ADAR1, although any mechanistic relationship remains undefined. Knockdown of METTL13 altered the expression of multiple genes involved in oncogenic development in HSPCs. Furthermore, METTL13 expression was associated with a high-risk profile in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and functional studies confirmed that METTL13 is required for T-ALL cell proliferation and survival both in vitro and in vivo. Collectively, our results identify METTL13 as a previously unrecognized regulator of leukemic transformation, independent of any presumed mechanistic interaction between RNA editing and m6A pathways.

DOI: https://doi.org/10.1038/s41419-026-08761-7
Cell Stem Cell. 2026 Apr 23. pii: S1934-5909(26)00122-0. [Epub ahead of print]

MMRN1-EGFR drives sialylglycan-Siglec immune evasion in AML leukemia stem cells.

Meixi Peng, Yongxiu Huang, Mengyun Zhang, Qinrong Yan, Lulu Li, Yaoqi Gui, Jingsong Cheng, Yanni Sun, Yi Mo, Wenqiong Xiang, Yongjie Zhang, Li Wang, Qin Wen, Xi Zhang, Yu Hou.

  Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) relapse and therapy resistance, predominantly through immune evasion. Here, we identify multimerin 1 (MMRN1) as being highly and specifically expressed in LSCs. Mechanistically, MMRN1 activates the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 1 (STAT1) pathway via its epidermal growth factor (EGF)-like domain, suppressing Neu5Ac degradation to drive sialylglycan accumulation, which forms glycoimmune checkpoints functionally akin to programmed death 1 (PD-1)/the cytotoxic T-lymphocyte antigen-4 (CTLA-4). These sialylglycans activate the sialylglycan-Siglec immune checkpoint axis, impairing T/natural killer (NK) cell activity and enabling LSC immune evasion. Additionally, MMRN1 sustains LSC self-renewal via the EGFR/STAT5/CD9 pathway. Genetic ablation of MMRN1 markedly suppresses AML progression and synergizes with anti-PD-L1/CTLA-4 therapy. In a clinical trial (ChiCTR2500097714), erlotinib (an EGFR inhibitor) combined with azacitidine plus the HAG regimen, which consists of homoharringtonine, a low dose of cytarabine, and granulocyte colony-stimulating factor priming, achieves a remission rate of 75% in relapsed/refractory AML, likely via MMRN1/EGFR axis blockade. Our findings establish MMRN1 as a dual-functional target for LSC maintenance and immune evasion and propose that disrupting MMRN1 or EGFR remodels the immunosuppressive tumor microenvironment, offering a promising strategy for AML immunotherapy.

Keywords:  MMRN1; immune escape; leukemia stem cell; sialylglycans; stemness

DOI:  https://doi.org/10.1016/j.stem.2026.03.012
Genes Dis. 2026 Jul;13(4): 101794

Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.

Agida Okohi Innocent, Yajie Shen, Yixuan Gao, Ruixin Sun, Kasimujiang Aximujiang, Zizhen Xu, Jinke Cheng, Jiao Ma.

  Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

Keywords:  AML branched-chain amino acids; Leukemogenesis; Oxidative stress; PI3K/AKT/mTORsignaling; UCP2

DOI:  https://doi.org/10.1016/j.gendis.2025.101794
Exp Hematol. 2026 Apr 17. pii: S0301-472X(26)00074-3. [Epub ahead of print] 105441

Stem11 score: towards rapid clinical prognostication for acute myeloid leukemia.

Tomoya Isobe, Manja Meggendorfer, Sebastian Wolf, Thomas Oellerich, Nicola K Wilson, Berthold Göttgens.

  Acute myeloid leukemia (AML) is an aggressive form of myeloid malignancy with high relapse and poor survival rates. Despite recent advances in genomics-based risk classification, accurate prediction of patient outcomes remains a challenge, posing the need for complementary molecular information to enable precise treatment stratification. In the current study, we assess the prognostic value of the recently developed 11-gene Stem11 signature in a uniformly treated cohort of 107 de novo AML patients and show that Stem11 classification stratifies overall survival and response to allogeneic hematopoietic cell transplantation across the European LeukemiaNet risk groups. We further develop a NanoString-based Stem11 scoring platform and validate its high concordance with RNA-sequencing-based scoring and its retained prognostic power to identify the most refractory AML subgroup. With its rapid turnaround time and standardized built-in analysis pipeline, our NanoString-based Stem11 scoring panel represents a faster yet reliable alternative to RNA-sequencing, providing preclinical proof of concept for Stem11-based clinical decision support. TEASER ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis. Current genetic risk stratification remains insufficient for accurately predicting patient outcomes, and additional information that can refine and improve prospective risk prediction is urgently needed. Here, we develop a NanoString-based diagnostic assay measuring the prognostic Stem11 score. Our assay provides highly concordant Stem11 scores with RNA-sequencing-based quantification, thereby establishing a rapid and reliable transcriptional prognostication system for time-sensitive clinical decision support for AML.

Keywords:  Gene expression; NanoString; Prognostication; acute myeloid leukemia

DOI:  https://doi.org/10.1016/j.exphem.2026.105441
Front Immunol. 2026 ;17 1730378

A comprehensive analysis of humanized mouse models for the study of cancer immunotherapies.

Philippe De La Rochere, Laure Loumagne, Melanie Rathaux, Marine Dubois, Jordan Denizeau, Fariba Nemati, Sophie Viel, Dario Rocha, Tamara Slavnic, Jayant Thatte, Henry Qixiang Li, Xuesong Ouyang, Christine Sedlik, Didier Decaudin, Georges Azar, Sukhvinder Sidhu, Eliane Piaggio.

   Introduction: Humanized immune system (HIS) mouse models, generated by engrafting tumors and hematopoietic cells of human (Hu) origin into immunodeficient host mice, effectively recapitulate key aspects of the crosstalk between human immune cells and tumors. These models represent a valuable tool for the preclinical evaluation of immunotherapies.
Methods: In this study, we provide a comprehensive comparison of two widely used HIS models: the Hu-CD34+ model, which engrafts Hu-hematopoietic cells derived from Hu-CD34+ hematopoietic stem cells (HSCs), and the Hu-PBMC model, which utilizes Hu-peripheral blood mononuclear cells (PBMCs).
Results: We assess the kinetics, quality and extent of immune cell engraftment, as well as the development of graft-versus-host disease (GVHD). Additionally, we investigate the impact of different immunodeficient host mouse strains on immune cell reconstitution in the Hu-CD34+ model. Both HIS models were engrafted with human tumors derived from either cell lines or patient-derived xenografts (PDX), revealing distinct immune-tumor interactions that influenced antitumor responses. Notably, tumor responses to T-cell-directed therapies, including anti-PD1 antibodies, IL-2-anti-IL-2 antibody complexes, and T-cell engagers, varied across these models.
Discussion: Our findings provide novel insights into the properties and limitations of HIS models, offering a critical resource for optimizing next-generation immuno-oncology strategies and guiding the design of future therapeutic interventions.

Keywords:  cancer; humanized mice; immune checkpoints; immunodeficient mice; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2026.1730378
Stem Cell Rev Rep. 2026 Apr 22.

Advancing Hematopoietic Stem Cell Research: The Impact of Bioengineered 3D Bone Marrow Niches.

Hridhya K Sidharthan, Mansi Goel, Manoj Unni, Neeraj Sidharthan, Binulal N Sathy.



Keywords:   Ex vivo HSC expansion; 3D bone marrow models; Bioengineered bone marrow niche; Bone marrow niche mechanobiology; Hematopoietic stem cell regulation; Niche-cell interactions

DOI:  https://doi.org/10.1007/s12015-026-11128-2
Protein Sci. 2026 May;35(5): e70553

Proteolytic control of mitochondrial protein translocases.

Lara Kroczek, Thomas Langer.

  Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.

Keywords:  mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control

DOI:  https://doi.org/10.1002/pro.70553
Hemasphere. 2026 Apr;10(4): e70358

Monocyte-mediated metabolic rewiring via CD31-CD38 interactions promotes growth and drug-resistance in multiple myeloma.

Ramin Raoof, Giada Dal Collo, Helga Simon-Molas, Panagiota Tzortzi, Konxhe Kulaj, Elif N Demirez, Crescenzo Massaro, Renée Poels, Charlotte L B M Korst, Chloe A O'Neill, Wassilis S C Bruins, Marloes E C Broekmans, Payam Behradkia, Maria Krevvata, Sonja Zweegman, Arnon P Kater, Serena R Baglio, Tuna Mutis, Niels W C J van de Donk.

Multiple myeloma (MM) cells interact with different components of the bone marrow (BM) microenvironment, which plays a critical role in MM progression and confers resistance to therapy. Here, we report that monocytes actively control MM cell metabolism by transferring mitochondria to MM cells, thereby increasing their mitochondrial content. Transfer of mitochondria required the expression of CD38 on the surface of MM cells and its ligand CD31 (PECAM-1) on monocytes. The mitochondrial increase in MM cells induced a boost in oxidative phosphorylation (OXPHOS). This monocyte-mediated metabolic adjustment promoted growth, motility, and drug-resistance in both MM cell lines and primary MM cells. Notably, the CD38-targeting monoclonal antibody daratumumab prevented mitochondrial transfer via blocking CD38 on MM cells. Furthermore, in the presence of daratumumab, monocytes acquired a divergent role and obtained mitochondria from MM cells through the process of trogocytosis. Daratumumab-mediated disruption of mitochondrial transfer reduced the mitochondrial content in MM cells, prevented the boost in OXPHOS, significantly impaired MM cell growth and migration, and mitigated drug-resistance. In conclusion, we reveal a crucial metabolic interplay between monocytes and MM cells within the BM microenvironment that promotes tumor growth and induces therapy resistance, providing the rationale for treatment strategies that combine targeting tumor metabolism with existing anti-MM agents.

DOI: https://doi.org/10.1002/hem3.70358
Cell Death Discov. 2026 Apr 24.

Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.

Alojzija Brcic, Hrvoje Lalic, Tomislav Smoljo, Klara Bardač, Vilma Dembitz, Romana Penker, Giovanny Rodriguez Blanco, Antonio Bedalov, Dora Visnjic.

Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress-driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine-purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses.

DOI: https://doi.org/10.1038/s41420-026-03105-y
Haematologica. 2026 Apr 23.

Bedaquiline amplifies proteasome inhibitor efficacy and overcomes resistance in multiple myeloma.

Michela Cumerlato, Monica Maccagno, María Labrador, Beatrice Luciano, Elisabetta Mereu, Mariangela Porro, Cecilia Bandini, Mattia Furlan, Domenico Maisano, Mattia D'Agostino, Alessandra Larocca, Francesca Gay, Annalaura Tamburrini, Francesca Anselmi, Paolo Ettore Porporato, Salvatore Oliviero, Benedetto Bruno, Eugenio Morelli, Nikhil Munshi, Roberto Piva.

Proteasome inhibitors (PIs) are cornerstone therapies for multiple myeloma (MM), yet resistance remains a major barrier to durable responses. To identify druggable vulnerabilities that enhance PI efficacy, we performed a small-molecule chemical screen in the presence of carfilzomib (CFZ). We identified bedaquiline (BDQ), an FDAapproved antimycobacterial agent, as a potent synergistic partner. BDQ and its fumarate salt (BDQ-F) significantly amplified CFZ-induced cytotoxicity in PI-sensitive and PI-resistant MM cells, in AL amyloidosis and other B-cell malignancies, with minimal toxicity toward normal cells. Mechanistic studies confirmed that BDQ specifically targets the ATP5F1C subunit of mitochondrial ATP synthase. BDQ-CFZ combination triggered extensive apoptosis, exacerbating proteotoxic stress and proteasome-associated pathways. BDQ specifically enhanced CFZ's inhibition of the proteasome's chymotrypsin-like activity. Importantly, BDQ synergized with multiple proteasome and ubiquitin-activating enzyme inhibitors, but not with other standard MM agents, underscoring its selective interaction with the UPS pathway. BDQ-CFZ cotreatment markedly reduced MM cell viability and tumor burden in patient-derived cells and zebrafish xenograft models. These findings support the therapeutic repurposing of BDQ to potentiate PI efficacy and overcome resistance in MM and related B-cell malignancies.

DOI: https://doi.org/10.3324/haematol.2025.300157
Protein Sci. 2026 May;35(5): e70587

Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.

Shunsuke Matsumoto, Suzuka Ono, Toshiya Endo.

  Mitochondria are enclosed by a double-membrane structure composed of the outer and inner membranes, and this architectural organization underlies their diverse cellular functions. In particular, the mitochondrial outer membrane serves as an essential interface between the cytosol and the mitochondrial interior, regulating the flux of proteins, lipids, small molecules, and ions through the coordinated activities of its resident proteome. Consequently, structural and functional defects of outer membrane proteins are subject to continuous surveillance, and aberrant proteins are rapidly recognized and degraded. Defects in precursor translocation or translation can lead to the stalling of precursor proteins at the primary protein import gate, the TOM complex. Such situations are resolved by multiple quality control systems operating across both the mitochondria and the cytosol. In addition, proteins normally destined for the endoplasmic reticulum or peroxisomes may be mistargeted to mitochondria, and these mislocalized proteins are likewise managed through dedicated mechanisms that promote their degradation or re-targeting. In this review, we summarize current insights into the molecular factors and mechanisms that maintain proteostasis at the mitochondrial outer membrane.

Keywords:  mitochondria; outer membrane; protein degradation; quality control; re‐targeting

DOI:  https://doi.org/10.1002/pro.70587
Nature. 2026 Apr 22.

Myosin forces remodel F-actin for mechanosensitive protein recognition.

Ayala G Carl, Matthew J Reynolds, Xiaoyu Sun, Pinar S Gurel, Donovan Y Z Phua, Keith Hamilton, Lin Mei, John W Watters, Yasuharu Takagi, Alex J Noble, James R Sellers, Gregory M Alushin.

Cells interface mechanically with their surroundings through cytoskeleton-linked adhesions1,2, which enable them to sense physical cues that instruct development and drive diseases such as cancer3-5. Contractile forces generated by myosin motor proteins6,7 mediate these mechanical signal transduction processes through unknown protein structural mechanisms. Here we show that force generated by myosin elicits structural changes in actin filaments (F-actin) that modulate binding by the mechanosensitive adhesion protein α-catenin8. Using correlative cryo-fluorescence microscopy and cryo-electron tomography, we identify F-actin featuring sinusoidal regions of nanoscale oscillating curvature at cytoskeleton-adhesion interfaces enriched in zyxin, a marker of actin-myosin-generated traction forces9. We introduce a reconstitution system for visualizing F-actin in the presence of myosin forces using cryo-electron microscopy, which reveals morphologically similar F-actin supercoils. In simulations, compressive forces that mimic myosin activity produce supercoils, which can be generated by ensembles of asynchronous motors regardless of their directionality. Three-dimensional reconstruction of supercoils uncovers extensive asymmetric remodelling of the helical lattice of F-actin. This is recognized by α-catenin, which binds cooperatively along individual strands, preferentially engaging interfaces that feature extended inter-subunit distances while simultaneously suppressing rotational deviations to regularize the lattice. In sum, we find that myosin forces can deform F-actin, generating a conformational landscape that is detected and reciprocally modulated by a mechanosensitive protein, providing a direct structural glimpse at active force transduction through the cytoskeleton.

DOI: https://doi.org/10.1038/s41586-026-10398-7
J Clin Invest. 2026 Apr 23. pii: e194427. [Epub ahead of print]

Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.

Adam Majcher, Ranjha Khan, Kathrin Buder, Florence Bourquin, Julie D Saba, Thorsten Hornemann.

  Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS) or nephrotic syndrome type 14 (NPHS14), is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enzyme responsible for the terminal degradation of sphingosine-1-phosphate (S1P). We investigated a patient carrying a previously undescribed c.1084T>A (p.Ser362Thr) SGPL1 variant and analyzed the metabolic and cellular consequences of SPL deficiency using patient fibroblasts, SGPL1-knockout HEK293T cells, and Sgpl1-/- and Sgpl1rosa+fl/fl mice. Metabolic stable isotope labelling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (i) feedback regulation of de novo sphingolipid synthesis via the ORMDL-ceramide axis and (ii) increased diversion of excess ceramides into glycosphingolipids. However, perturbation of sphingolipid homeostasis - either by exogenous sphingolipid load or disruption of compensatory regulation - induces pathological intracellular S1P accumulation. In vivo, Sgpl1-/- mice exhibited pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho-ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation. Pharmacological ROCK inhibition with Fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture. These findings redefine the metabolic consequences of SPL deficiency and identify S1P-driven Rho-ROCK hyperactivation as a tractable therapeutic target in SPLIS.

Keywords:  Chronic kidney disease; Cytoskeleton; Genetics; Lipidomics; Metabolism; Nephrology

DOI:  https://doi.org/10.1172/JCI194427
Nat Commun. 2026 Apr 23. pii: 3474. [Epub ahead of print]17(1):

Single cell transcriptional evolution of myeloid leukemia of Down syndrome.

Mi K Trinh, Konstantin Schuschel, Hasan Issa, Rebecca Thomas, Conor Parks, Agnes Oszlanczi, Toochi Ogbonnah, Di Zhou, Lira Mamanova, Elena Prigmore, Emilia R Robertson, Angus Hodder, Anna Wenger, Nathaniel D Anderson, Holly J Whitfield, Taryn D Treger, José Gonçalves-Dias, Karin Straathof, David O'Connor, Matthew D Young, Laura Jardine, Stuart Adams, Jan-Henning Klusmann, Jack Bartram, Sam Behjati.

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), via a conserved sequence of mutations. Here, we examine the relationship between the genetic and transcriptional evolution of ML-DS from natural variation; a rich collection of primary patient samples and foetal tissues with a range of constitutional karyotypes. We distil transcriptional consequences of each genetic step in ML-DS evolution, utilising single-cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We find that transcriptional changes induced by the TAM-defining GATA1 mutations are retained in, and account for most of the ML-DS transcriptome. The GATA1 transcriptome pervades all stages of ML-DS, including progressive disease that had undergone genetic evolution. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distiling consequences of mutations within their pathophysiological context.

DOI: https://doi.org/10.1038/s41467-026-71707-2
Cell Rep Med. 2026 Apr 20. pii: S2666-3791(26)00173-4. [Epub ahead of print] 102756

A 15-layer multi-omics analysis of gastric cancer ecotypes provides therapeutic insights.

Clinical Proteomic Tumor Analysis Consortium

  Gastric cancer is marked by profound molecular and microenvironmental heterogeneity that limits therapeutic progress. Here, we present a 15-layer multi-omics atlas that integrates genomics, epigenomics, transcriptomics, proteomics, multiple post-translational modifications (PTMs), protein-protein interactions, metabolomics, and microbiome profiles from 159 primary gastric adenocarcinomas and 30 matched normal adjacent tissues. Using cell-state deconvolution, we define tumor ecotypes that refine genomic and histological subtypes by capturing distinct tumor microenvironment architectures linked to clinical outcomes and potential associations with immunotherapy response. Multi-omics integration prioritizes genomic and epigenomic aberrations and their associated vulnerabilities; defines ecotype-specific transcriptional programs, signaling pathways, PTMs, protein interaction networks, and metabolic regulation; and identifies microbiome features linked to ecotypes and resistance pathways. We further prioritize ecotype-, genomic subtype-, and cell type-specific targetable proteins using proteomic and PTM analyses within a tumor microenvironment context. This comprehensive atlas provides a systems-level blueprint for decoding gastric cancer heterogeneity and advancing precision oncology.

Keywords:  gastric cancer; metabolomics; microbiome; multi-omics; post-translational modifications; precision oncology; protein-protein interactions; proteogenomics; therapeutic targets; tumor ecotypes; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2026.102756
Genome Biol. 2026 Apr 21.

Full-DIA enables complete single-cell proteomics from diaPASEF using deep learning.

Jian Song, Amanda Momenzadeh, Hebin Liu, Chengpin Shen, Jesse G Meyer, Xiaohui Wu.

diaPASEF improves ion utilization and sensitivity by synchronizing quadrupole isolation with trapped ion mobility separation, making it suitable for single-cell proteomics. We present Full-DIA, a deep learning-driven software that enhances proteome coverage, quantitative accuracy, and analysis speed over DIA-NN for single-cell diaPASEF data. Notably, Full-DIA generates a missing-value-free protein matrix under stringent global FDR control, enabling downstream analyses without data gaps. Applied to LPS-treated and cell-cycle datasets, this matrix yields pathway enrichment results with fewer off-target and more biologically relevant pathways. Full-DIA highlights the potential of deep learning for four-dimensional diaPASEF analysis and offers a solution to missing values.

DOI: https://doi.org/10.1186/s13059-026-04087-x
Bioconjug Chem. 2026 Apr 24.

Visualizing Newly Synthesized Proteins and Their Degradation Dynamics by Using Long-Wavelength-Emitting Fluorescent Dye-DBCO Conjugates.

Shun Sumitani, Eita Sasaki, Hisashi Ohno, Sota Yamada, Orie Takayama, Fan-Yan Wei, Yoshihiko Kuchitsu, Tomohiko Taguchi, Kenjiro Hanaoka.

Understanding the spatiotemporal dynamics of protein synthesis and degradation is important for establishing how cells maintain protein homeostasis. Conventional methods for detecting newly synthesized proteins include metabolic labeling with radioactive [35S]methionine (Met) or the incorporation of l-azidohomoalanine (AHA) or l-homopropargylglycine followed by fluorescent labeling via copper(I)-catalyzed click chemistry. However, these methods typically require cell fixation, making them unsuitable for live-cell imaging. Here, we describe a fluorescence imaging technique to monitor newly synthesized proteins in living cells by utilizing a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction, in which l-AHA-containing proteins are labeled with fluorescent dyes conjugated to dibenzocyclooctyne (DBCO). We synthesized orange-emitting tetramethylrhodamine (TAMRA)-DBCO and far-red-emitting silicon rhodamine (SiR)-DBCO. TAMRA-DBCO enabled the visualization of newly synthesized proteins and their time-dependent degradation throughout the entire cell. SiR-DBCO was similarly effective, but was mainly distributed to the cytoplasm. The time-dependent decrease of TAMRA-DBCO fluorescence intensity in living cells was suppressed by lysosomal enzyme inhibitors and a proteasome inhibitor, suggesting that newly synthesized proteins are degraded via both pathways. Moreover, imaging of drug-induced senescent cells with TAMRA-DBCO suggested that senescent cells have a lower protein degradation ability than nonsenescent cells. These methods should be useful for investigating protein homeostasis in living cells.

DOI: https://doi.org/10.1021/acs.bioconjchem.5c00645
Mol Cell Proteomics. 2026 Apr 22. pii: S1535-9476(26)00068-X. [Epub ahead of print] 101572

Surfaceome Capture by Multiplex biotinylation (SUCAM) enables enhanced identification of cell surface proteins by mass spectrometry.

Ana Levi, Tommy Shields, Irbaz I Badshah, Vinothini Rajeeve, Pedro R Cutillas.

  A key goal of surfaceomic discovery technologies is to comprehensively interrogate the cell surface proteome to identify targets for immunotherapy development. Considerable progress has made in the application of surfaceomics to profile cancer cells. However, challenges still exist in the sensitivity of current surfaceomic approaches, which consequently, are restricted to the analysis of cell lines or primary tumour material that contain a relatively large number of cells. In addition, since current approaches are based on labelling a single functional group on polypeptides, it is not clear if these recover the full spectrum of proteins present on cell surfaces. To circumvent these limitations, we developed a biotinylation-based combinatory approach for isolating a more diverse group of proteins facing the cell periphery. Our proposed approach, named Surfaceome Capture by Multiplex (SUCAM) biotinylation consists of "multiplexing" biotin reagents to enable for multiple-functional group derivatisation of the surface proteome. LC-MS/MS is then used to identify and characterize proteins pulled down by streptavidin magnetic beads. We found that SUCAM identified more plasma membrane and cell surface proteins than methods based on labelling with single reagents, leading to enhanced identification of cell surface proteins from just 1.2 million cells. Replicate experiments revealed that surfaceomic proteins could be quantified with good precision across repeats (coefficient of variation of 1.7% on average). Application of the approach to a panel of leukaemia cell lines identified well-known leukemic cell surface antigens, as well as proteins with hitherto uncharacterised roles in this disease. SUCAM is a complementary biotinylating strategy that will facilitate surfaceomic profiling for discovery of therapeutic targets in haematological and solid tumours.

Keywords:  cancer; drug target; immunotherapy; leukaemia; quantitative proteomics; surfaceomics

DOI:  https://doi.org/10.1016/j.mcpro.2026.101572
Nat Commun. 2026 Apr 20.

Salicylic acid modulates its catabolic enzymes via proteasomal degradation linked to SCF-associated proximity networks.

Natalie Hamada, Malathy Palayam, Jacob Moe-Lange, Gabrielle Wyatt, Christian Montes, Sun Hyun Chang, Annie Hu, Savithramma P Dinesh-Kumar, Philipp Zerbe, Justin W Walley, Nitzan Shabek.

Salicylic acid (SA) is a central regulator of plant immunity, and precise control of its levels is essential to balance defense and growth. However, the mechanisms controlling the stability and abundance of SA-catabolizing enzymes remain elusive. Here we show that the SA hydroxylases DOWNY MILDEW RESISTANT 6 (DMR6) and DMR6-LIKE OXYGENASE 1 (DLO1) are targeted for ubiquitin-proteasome-dependent degradation. SA promotes DMR6 turnover but stabilizes DLO1, linking catalytic activity and conformational dynamics to protein fate. Structural and biochemical analyses indicate that SA binding induces conformational changes in DMR6, particularly in a conserved C-terminal helix, which may contribute to its susceptibility to degradation. Proximity labeling of DMR6 and DLO1 identified a previously uncharacterized Kelch-type F-box protein, which we designate as DMR6-ASSOCIATED F-BOX 1 (DAF1), that contributes to SCF-type E3 ligase-mediated proteasomal turnover of DMR6 in planta, thereby modulating SA-mediated cell death. Complementary proximity labeling of the SCF adaptor ASK1 in Arabidopsis during Pseudomonas syringae infection uncovered remodeling of F-box networks while consistently recovering DMR6 and DLO1, highlighting their integration within immune-responsive proteolytic circuits. These findings support a self-limiting regulatory circuit in which SA simultaneously induces and destabilizes its catabolic enzymes, coupling hormone metabolism with proteasome-mediated control of immune homeostasis.

DOI: https://doi.org/10.1038/s41467-026-72241-x
Nat Rev Cancer. 2026 Apr 24.

The sleeping threat: targeting cancer dormancy to transform metastasis therapy.

Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero, Wenjun Guo, Gregoire Lauvau, Maria Soledad Sosa.

Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.

DOI: https://doi.org/10.1038/s41568-026-00928-w