bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–02–22
forty-five papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
  2. Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
  3. Expansion microscopy (ExM) of lipids for super-resolution imaging of membranes.
  4. High-Sensitive Spatial Proteomics for Pancreatic Cancer Progression Analysis.
  5. Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux.
  6. Melatonin-Induced Modulation of Cholesterol-Enriched Model Neuronal Membranes.
  7. GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer.
  8. The integrated stress response promotes immune evasion through lipocalin 2.
  9. The Lipid Interactome: An interactive and open access platform for exploring cellular lipid-protein interactions.
  10. Decoding cancer across scales with metabolomics.
  11. Sympathetic nerve-fibroblast crosstalk drives nerve injury, fibroblast activation, and matrix remodeling in pancreatic cancer.
  12. Imaging oxidative and nitrative stress in membranes.
  13. Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
  14. Human neuromuscular organoids mimic cancer-induced muscle cachexia.
  15. Core principles of autophagy initiation mechanisms.
  16. Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer.
  17. TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition.
  18. Subcellular localization as a driver of protein function.
  19. A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.
  20. The pancreatic cancer drug market.
  21. Geometry of disordered porous environments regulates cell migration.
  22. Visualization of single-cell lipidomes with MALDI-MSI.
  23. Structural basis of caveolin-driven membrane bending.
  24. MEK inhibitor-based genomically matched combinatorial targeted therapies in metastatic pancreatic adenocarcinoma with KRAS alterations.
  25. A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
  26. Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
  27. DETERGENTS WITHOUT A DRAIN: THE EVOLUTIONARY LOGIC (AND LIABILITY) OF SPHINGOLIPIDS.
  28. Eythrocyte-anti-PD1 conjugates in persons with advanced solid tumors resistant to anti-PD1/PDL1: preclinical characterization and results of a phase 1 trial.
  29. pmultiqc: An open-source, lightweight, and metadata-oriented QC reporting library for MS proteomics.
  30. Alkyne lipids as tracers of lipid metabolism.
  31. Lipidation as a post-translational code for protein liquid-liquid phase separation.
  32. Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
  33. Metabolic labeling of glycerophospholipids.
  34. Lipid droplet-induced T cell death sustains autoimmune tissue inflammation.
  35. Evidence that extra copies of chromosome 1q play a role in the early phases of pancreatic neoplasia.
  36. Non-invasive imaging of phosphoinositides with genetically encoded lipid biosensors.
  37. Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties.
  38. Membrane composition-dependent patterning of Rho and F-actin in an artificial cell cortex.
  39. A two-step clockwork mechanism opens a proteo-lipidic pore in PIEZO2.
  40. Strategies to minimize artificial lipid oxidation in mass spectrometry based epilipidomics analysis.
  41. Tuning the sensitivity of mechanosensory receptors through histidine scanning.
  42. CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis.
  43. InSituPy: A framework for histology-guided, multi-sample analysis of single-cell spatial omics data.
  44. STING ablation in T cells is required for the efficacy of STING agonists in CAR-T cell immunotherapy of pancreatic cancer.
  45. A Membrane-Impermeable Near-Infrared Probe Enables High-Fidelity Tracking of Foam Cell Progression.
  1. Dev Cell. 2026 Feb 17. pii: S1534-5807(26)00037-7. [Epub ahead of print]
    Ferroptosis induces heterogeneous death profiles that are controlled by lysosome rupture.
    Jyotirekha Das, Saloni K Hombalkar, Alison D Klein, Esraa Nsasra, Muskaan Vasandani, Kay Petruzzi, Dajun Lu, Stephen Ruiz, Orit Kliper-Gross, Jiachen Hu, Michelle Riegman, Xuejun Jiang, Daniel A Heller, Assaf Zaritsky, Michelle S Bradbury, Michael Overholtzer.
      Ferroptosis is a lipid peroxide-dependent form of cell death that occurs in degenerative conditions and may be leveraged for cancer therapy. Although numerous regulators are known to control its cell-autonomous execution, ferroptosis also has a collective property that involves propagation between cells, and this regulation has remained more obscure. Different modes of ferroptosis induction involving inhibition of the anti-ferroptotic enzyme GPX4 or depletion of glutathione can impact the collective death response differently, but the mechanisms underlying "single-cell" versus "propagative" ferroptosis are not well understood. Here, we discover significant lysosome rupture occurring during propagative ferroptosis and identify glutathione depletion as sufficient to convert GPX4 inhibition from an individual-cell response to a collective response. We find that induction of single-cell ferroptosis involves heterogeneous death profiles, with necrosis and apoptosis occurring in parallel within cell populations. These findings identify factors that control propagation and underscore lysosomes as critical to the execution of ferroptosis.
    Keywords:  GPX4; TFEB; apoptosis; cathepsin; ferroptosis; iron; lipid peroxidation; lysosome; necrosis; propagation
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.014
  2. bioRxiv. 2025 Dec 03. pii: 2025.12.01.691597. [Epub ahead of print]
    Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
    Matias Fabregat, Rachel J Fenske, Julia K Hansen, Cameron J Kaminsky, Jevin Lortie, Alexander Nassar, Kayla Kressin, Annie Jen, Lucia Cilloni, Katherine Overmeyer, Caroline M Alexander, John W Garrett, Perry J Pickhardt, Joshua J Coon, Costas A Lyssiotis, Marina Pasca di Magliano, Lingjun Li, Adam J Kuchnia, Andrea Galmozzi.
      Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.
    DOI:  https://doi.org/10.64898/2025.12.01.691597
  3. Methods Enzymol. 2026 ;pii: S0076-6879(25)00485-9. [Epub ahead of print]726 19-44
    Expansion microscopy (ExM) of lipids for super-resolution imaging of membranes.
    Aakriti Garg, Brittany M White-Mathieu.
      Lipid Expansion Microscopy (LExM) is a super-resolution imaging technique that enables nanoscale visualization of cellular membranes in cultured cells using confocal microscopy. The procedure relies on the preservation and anchoring of lipids into a swellable hydrogel that is physically expanded to increase resolution. By labeling lipids with alkyne functional groups and covalently anchoring these bioorthogonally labeled lipids into a hydrogel network via copper-catalyzed azide-alkyne cycloaddition (CuAAC) with a trifunctional probe, LExM facilitates direct, super-resolution imaging of membrane ultrastructure. This chapter presents a comprehensive protocol for (i) labeling of cellular membranes with phospholipid precursors and cholesterol analogs, (ii) click chemistry tagging with a trifunctional, fluorophore-bearing probe, (iii) hydrogel embedding, (iv) expansion, and (v) imaging. The method enables detailed membrane visualization at sub-diffraction resolution via 4-7.8x sample expansion, is compatible with standard fluorescence microscopy, and is adaptable to multiplexed imaging of protein-lipid colocalization.
    Keywords:  Click chemistry; Fluorescence imaging; Lipid expansion microscopy; Membranes; Nanoscale; Super-resolution
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.004
  4. Anal Chem. 2026 Feb 18.
    High-Sensitive Spatial Proteomics for Pancreatic Cancer Progression Analysis.
    Jongmin Woo, Zhenyu Sun, Yingwei Hu, Trung Alvin Hoàng, Christine Worthington, Katelyn Smith, Aatur Singhi, Randall E Brand, Daniel W Chan, Qing Kay Li, Ralph H Hruban, Hui Zhang.
      Pancreatic cancer remains one of the most challenging malignancies to diagnose and treat due to the late development of symptoms and limited early diagnostic options. Intraductal papillary mucinous neoplasms (IPMNs) are noninvasive precursors to invasive pancreatic ductal adenocarcinoma (PDAC), and an understanding of the changes in patterns of protein expression that accompany the progression from normal ductal (ND) cells to IPMN and PDAC may provide avenues for improved earlier detection. In this study, we present an optimized spatial tissue proteomics workflow, termed SP-Max (Spatial Proteomics Optimized for Maximum Sensitivity and Reproducibility in Minimal Sample), designed to maximize protein recovery and quantification from limited laser microdissected (LMD) samples. Our workflow enabled the identification of more than 6000 proteins and the quantification of over 5200 protein groups from FFPE tissue contours of pancreatic tissues. Comparative analyses across ND, IPMN, and PDAC revealed critical molecular differences in protein pathways and potential markers of progression. SP-Max provides a systematic, reproducible approach that markedly enhances our ability to study precancerous lesions and cancer progression in pancreatic tissues at high resolution.
    DOI:  https://doi.org/10.1021/acs.analchem.5c01928
  5. Cell. 2026 Feb 16. pii: S0092-8674(25)01502-8. [Epub ahead of print]
    Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux.
    Mohamad Assi, Ruohong Wang, Emily A Kawaler, Albert S W Sohn, M Zahidunnabi Dewan, Despoina Kalfakakou, Joel Encarnacion-Rosado, Kevin S Kapner, Koelina Ganguly, Joao A Paulo, Diane M Simeone, Andrew J Aguirre, Robert S Banh, Alec C Kimmelman.
      Autophagy, a programmed self-eating process, underlies the progression of multifactorial diseases like pancreatic ductal adenocarcinoma (PDA). Except for nutrient availability, the contribution of microenvironmental factors to autophagy regulation is not well understood. Through integrating functional genomics and tumor-like 3D cultures, we show that human PDA cells regulate their autophagy levels by sensing the extracellular matrix (ECM) via the integrinα3-Hippo-YAP1 axis. The spatial proximity of PDA cells to the ECM shapes their intracellular autophagy levels, leading to heterogeneous biological responses. Specifically, PDA cells with low autophagy levels are proliferative, whereas those with high autophagy levels display better tolerance to chemotherapies. Targeting the ECM-mediated autophagy regulation reduces autophagic heterogeneity, alters PDA growth, and shapes antitumor responses to FDA-approved therapies. In summary, we have characterized a non-metabolic regulation of autophagy through ECM sensing, opening the possibility to investigate and target ECM-specific outputs in diseases.
    Keywords:  autophagy; cancer; extracellular matrix sensing; fibrosis; lysosome
    DOI:  https://doi.org/10.1016/j.cell.2025.12.053
  6. ACS Chem Neurosci. 2026 Feb 18.
    Melatonin-Induced Modulation of Cholesterol-Enriched Model Neuronal Membranes.
    Dima Bolmatov, Russel J Reiter, Dmitry Zav'yalov, Changwoo Do, Gergely Nagy, Charles Patrick Collier, John Katsaras, Maxim O Lavrentovich.
      Melatonin, a hormone primarily produced by the brain's pineal gland, not only regulates circadian rhythms, but also influences the structural and biophysical properties of neuronal membranes. Its amphiphilic nature enables direct incorporation into lipid bilayers and preferential interactions with cholesterol-rich lipid rafts, critical hubs for cellular signaling and membrane organization. Despite increasing recognition of its membrane activity, the molecular basis of melatonin's interactions with coexisting liquid-ordered (Lo) and liquid-disordered (Ld) phases remains unclear. Here, we combine small-angle neutron scattering (SANS) and all-atom molecular dynamics simulations to examine model neuronal membranes composed of DSPC, DOPC, POPC, and cholesterol. Our results show that melatonin preserves domain morphology while adopting distinct orientations within the bilayer and at the membrane interface, allowing both lateral and transmembrane bridging across lipid phases. These findings establish the molecular underpinnings of melatonin's modulation of membrane heterogeneity and provide strong support for its receptor-independent actions.
    Keywords:  atomistic simulations; cholesterol; melatonin; neuronal membranes; neutron scattering; phase separation
    DOI:  https://doi.org/10.1021/acschemneuro.5c00682
  7. Adv Sci (Weinh). 2026 Feb 17. e23198
    GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer.
    Marie Sabatier, Mayher Kaur, Milena Chaufan, Felix-Levin Hormann, Luiza Martins Nascentes Melo, Mario Palma, Jordan Torpey, Yanshan Liang, Alanis Carmona, Cameron Fraser, Midori Flores, Krystina J Szylo, Mahsa Yavari, Sheng Hui, Alpaslan Tasdogan, Sven Heiles, Jessalyn M Ubellacker.
      Leveraging ferroptosis as a cancer therapy has faced challenges due to the limited bioavailability and systemic toxicities of small-molecule ferroptosis modulators. Small molecule inhibitors such as RSL3 and ML210 trigger ferroptosis by targeting glutathione peroxidase 4 (GPX4), a key enzyme that neutralizes lipid peroxides. While many studies have focused on targeting primary tumors, much less is known about the extent to which GPX4-inhibitor resistance may contribute to metastasis. To address this, we cultured triple-negative breast cancer cell lines with GPX4 inhibitors to generate cell lines (M231, 4T1) that were resistant to GPX4 inhibitors (GPX4i). Tumors derived from GPX4i-resistant cells compared to parental cells had unique metabolic and lipidomic profiles, were associated with a shift toward an epithelial-like state (decreased vimentin, increased EpCAM expression), formed decreased spontaneous metastases from primary tumors, but had no differences in overall metastatic burden upon intravenous injection. Collectively, these data demonstrate that long-term maintenance with GPX4-inhibitors in vitro leads to altered metastatic profiles in vivo.
    Keywords:  ferroptosis; lipid peroxidation; metastases; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202523198
  8. Nature. 2026 Feb 18.
    The integrated stress response promotes immune evasion through lipocalin 2.
    Jozef P Bossowski, Ray Pillai, John Kilian, Angela Wong Lau, Mari Nakamura, Ali Rashidfarrokhi, Yuan Hao, Ruxuan Li, Katherine Wu, Takamitsu Hattori, Eliezra Glasser, Akiko Koide, Lidong Wang, Andre L Moreira, Cristina Hajdu, Sahith Rajalingam, Sarah E LeBoeuf, Hortense Le, Seungeun Lee, Jin Woo Oh, Cheolyong Joe, Hyemin Kim, Chan-Young Ock, Se-Hoon Lee, Hao Wang, Angana A H Patel, Volkan I Sayin, Aristotelis Tsirigos, Kwok-Kin Wong, Sergei B Koralov, Mario Pende, Francisco J Sánchez-Rivera, Diane M Simeone, Ioannis K Zervantonakis, Shohei Koide, Thales Papagiannakopoulos.
      Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.
    DOI:  https://doi.org/10.1038/s41586-026-10143-0
  9. Bioinformatics. 2026 Feb 18. pii: btaf651. [Epub ahead of print]
    The Lipid Interactome: An interactive and open access platform for exploring cellular lipid-protein interactions.
    Gaelen Guzman, André Nadler, Frank Stein, Jeremy M Baskin, Carsten Schulz, Fikadu G Tafesse.
      Lipid-protein interactions play essential roles in cellular signaling and membrane dynamics, yet their systematic characterization has long been hindered by the inherent biochemical properties of lipids. Recent advances in functionalized lipid probes-equipped with photoa  c  tivatable crosslinkers, affinity handles, and photocleavable protecting groups-have en  a  bled proteomics-based identification of lipid interacting proteins with unprecedented spec  i  ficity and resolution. Despite the growing number of published lipid interactomes, there r  e  mains no centralized effort to harmonize, compare, or integrate these datasets. The Lipid Interactome addresses this gap by providing a structured, interactive web portal that a  d  heres to FAIR data principles-ensuring that lipid interactome studies are Findable, Acce  s  sible, Interoperable, and Reusable. Through standardized data formatting, interactive vis  u  alizations, and direct cross-study comparisons, this resource enables researchers to sy  s  tematically explore the protein-binding partners of diverse bioactive lipids. By consolidating and curating lipid interactome proteomics data from multiple studies, the Lipid Interactome database serves as a critical tool for deciphering the biological functions of lipids in cellular systems.
    AVAILABILITY: This site can be viewed at LipidInteractome.org all data is available for dow  n  load. No user information is collected or necessary for data navigation, interaction, or dow  n  load.
    DOI:  https://doi.org/10.1093/bioinformatics/btaf651
  10. Nat Rev Cancer. 2026 Feb 20.
    Decoding cancer across scales with metabolomics.
    Joe L Rowles, Gary J Patti.
      It is well established that malignant cells alter their metabolism to support proliferation, but the nutrients required to meet the anabolic demands of different cancers located at various anatomical sites throughout the body remain largely unknown. Moreover, the extent to which nutrients are supplied by neighbouring stromal cells or distant tissues, possibly due to metabolic reprogramming, is poorly understood. Metabolomics provides a unique biochemical approach to address these gaps in our knowledge, but cancer studies require careful consideration because it is challenging to identify appropriately matched control samples for comparison. Here, we detail a collection of metabolomics workflows designed to interrogate cancer across three discrete scales. First, we describe experiments to define the nutrient demands of cancer cells themselves. Second, we focus on identifying metabolic relationships between neighbouring cells in the tumour microenvironment. Finally, we highlight strategies to explore the metabolic crosstalk between cancer cells and distant tissues in the tumour macroenvironment. The approaches outlined span cells in culture, animal models and human specimens from patients with cancer. Special emphasis is dedicated to the application of emerging technologies and computational pipelines in the field of mass spectrometry that enable global profiling of metabolites and lipids.
    DOI:  https://doi.org/10.1038/s41568-026-00908-0
  11. JCI Insight. 2026 Feb 19. pii: e192814. [Epub ahead of print]
    Sympathetic nerve-fibroblast crosstalk drives nerve injury, fibroblast activation, and matrix remodeling in pancreatic cancer.
    Ariana L Sattler, Parham Diba, Kevin Hawthorne, Carl Pelz, Joe Grieco, Tetiana Korzun, Bryan Chong, M J Kuykendall, Rosalie C Sears, Daniel L Marks, Mara H Sherman, Teresa A Zimmers, S Ece Eksi.
      Pancreatic cancer is a highly innervated gastrointestinal disease in which sympathetic nerves play a critical role in modulating tumor growth and the tumor microenvironment (TME). While recent studies suggest that sympathetic nerves influence various TME components, including lymphoid and myeloid immune cells, their interactions with cancer-associated fibroblasts (CAFs) remain poorly understood. CAFs are a hallmark of pancreatic tumors and are known to upregulate axon guidance and neuroactive cues, suggesting a potential feedback loop with tumor-innervating nerves. Here, we investigated the bidirectional crosstalk between sympathetic nerves and CAFs in human and mouse pancreatic tumors. Using a chemo-genetic ablation model, we selectively eliminated pancreatic sympathetic nerves and found that denervation significantly reduced tumor size in female mice. To further dissect this interaction, we established co-culture systems with immortalized pancreatic fibroblasts and primary sympathetic neuron explants, identifying key transcriptional changes driven by CAF-sympathetic nerve signaling. Our findings demonstrated that sympathetic signaling enhanced CAF activation and extracellular matrix remodeling, while activated CAFs, in turn, induced transcriptional programs in sympathetic neurons associated with nerve injury response. These results establish CAFs as central mediators of the tumor-supportive role of sympathetic nerves, offering further insights into the neural regulation of pancreatic cancer progression.
    Keywords:  Cancer; Cell biology; Mouse models; Neuroscience; Oncology; Transcriptomics
    DOI:  https://doi.org/10.1172/jci.insight.192814
  12. Methods Enzymol. 2026 ;pii: S0076-6879(25)00487-2. [Epub ahead of print]726 114-142
    Imaging oxidative and nitrative stress in membranes.
    Liming Wang, Enver Cagri Izgu.
      Membrane integrity is essential for cellular homeostasis, signal transduction, and cell-to-cell communication. Dysregulated and excessive production of reactive oxygen and nitrogen species causes oxidative, nitrative, or nitrosative stress, which can damage membranes. Investigations of redox species in lipid compartments therefore advance the understanding of complex redox biochemistry and how it impacts membranes at the organelle, cellular, and tissue levels. Phospholipid-based redox probes that are based on a natural lipid architecture can offer reliable detection of redox species interacting with membranes. These lipidoids and their fluorescently activated products can localize specifically within bilayer membranes, allowing site-specific imaging. We describe detailed steps for the use of designer lipidoids to image biomimetic membranes and subcellular compartments of live mammalian cells under redox stress. In addition, we present a synopsis of how these lipidoids are chemically prepared and utilized to detect nitrative stress on the epithelial surface of the lungs.
    Keywords:  Activity-based sensing; Endoplasmic reticulum; Fluorescence imaging; Lipid compartments; Lipid nanoparticles; Lipidoid; Lung tissue; Nitrative stress; Oxidative stress; Redox probe
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.006
  13. Nat Metab. 2026 Feb 20.
    Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
    Caroline A M Weiss, Lauryn A Brown, Lucas Miranda, Paolo Pellizzoni, Sophia Steigerwald, Kirsten Remmert, Jonathan M Hernandez, Karsten Borgwardt, David E Kleiner, Shani Ben-Moshe, Florian A Rosenberger, Natalie Porat-Shliom, Matthias Mann.
      Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here we show the application of single-cell Deep Visual Proteomics to perform spatially resolved proteome analysis of individual cells in native liver tissue. We built a robust framework comprising strategic cell selection and continuous protein gradient mapping, allowing the investigation of larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analysing hundreds of isolated hepatocytes from 18 individuals. Among the 2,500 proteins identified per cell, about half exhibited zonated expression patterns. Cross-species comparison with male mice revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of samples with disrupted liver architecture demonstrated widespread loss of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive and open-access resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.
    DOI:  https://doi.org/10.1038/s42255-026-01459-2
  14. Cell Rep Methods. 2026 Feb 17. pii: S2667-2375(26)00031-7. [Epub ahead of print] 101331
    Human neuromuscular organoids mimic cancer-induced muscle cachexia.
    Pietro Chiolerio, Beatrice Auletta, Camilla Pezzini, Luigi Sartore, Giorgia Gregolon, Onelia Gagliano, Cecilia Laterza, Valeria Roxana Balmaceda Valdez, Davide Cacchiarelli, Camilla Luni, Carlo Viscomi, Melanie Planque, Sarah-Maria Fendt, Marco Sandri, Roberta Sartori, Anna Urciuolo.
      Cancer cachexia, a devastating metabolic wasting syndrome affecting up to 80% of solid cancer patients, remains incurable despite advances in tumor biology understanding. This study introduces neuromuscular organoids (NMOs) derived from human-induced pluripotent stem cells (hiPSCs) as a platform to investigate cancer-driven muscle cachexia. We found that NMOs respond well to atrophic stimuli and replicate the key features of cancer cachexia when treated with conditioned media derived from cachexia-inducing cancer cells. Specifically, cachectic NMOs showed muscle mass loss, impairment of muscle contraction, alteration of intracellular calcium homeostasis, appearance of mitochondrial dysfunction with a metabolic shift, and enhancement of autophagy. Based on these results, we propose NMOs derived from hiPSCs as an in vitro tool for investigating human muscle cachexia, with potential future avenues of patient-specific modeling and therapeutic screening.
    Keywords:  CP: cancer biology; CP: stem cell; autophagy; cancer cachexia; human induced pluripotent stem cells; in vitro human disease model; metabolic remodeling; mitochondrial dysfunction; neuromuscular junction; neuromuscular organoid; skeletal muscle wasting
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101331
  15. Nat Struct Mol Biol. 2026 Feb 20.
    Core principles of autophagy initiation mechanisms.
    Tetsuya Kotani, Hitoshi Nakatogawa.
      Autophagy is a conserved intracellular degradation system essential for maintaining cellular homeostasis and adapting to a variety of environmental or metabolic cues. Different types of autophagy are induced in response to various physiological signals through distinct mechanisms. In this Review, we highlight recent advances in understanding the molecular mechanisms that induce autophagic degradation of cytoplasmic material in bulk upon nutrient or energy deprivation, and those that trigger the selective autophagic removal of specific cellular components for their quality or quantity control. We discuss mechanistic principles shared across different types of autophagy, such as phase-separation-mediated assembly and activation of related factors, and the coordination between cargo recognition and membrane biogenesis, delineating how diverse mechanisms converge on core principles to ensure context-specific control of autophagy initiation.
    DOI:  https://doi.org/10.1038/s41594-026-01752-4
  16. Cell Rep Med. 2026 Feb 17. pii: S2666-3791(26)00030-3. [Epub ahead of print]7(2): 102613
    Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer.
    Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Yue Zeng, Xiaofei Wang, Jun Yao, Jennifer Li, Prapassorn Thirasastr, Jangho Park, Yangxi Zheng, Long T Vien, Khalida M Wani, Huamin Wang, Sisi Gao, Tim Heffernan, Lawrence Kwong, Ignacio I Wistuba, Laura Bover, Giulio F Draetta, Haoqiang Ying, Wantong Yao.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge. We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth. Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo. Mechanistically, the anti-SDC1 mAb blocks macropinocytosis and induces antibody-dependent cellular cytotoxicity (ADCC). In vivo, anti-SDC1 mAb synergizes with standard chemotherapy, KRAS∗ inhibitors, and immunotherapies, resulting in tumor regression and near-complete response. These findings highlight the anti-SDC1 mAb as a promising therapeutic strategy for PDAC and potentially other KRAS∗ and SDC1-driven tumors.
    Keywords:  Syndecan-1; immunotherapy; macropinocytosis; natural killer cells; pancreatic cancer; therapeutic antibody
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102613
  17. EMBO J. 2026 Feb 19.
    TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition.
    Eva-Maria Weiden, Zala Serianz, Yvonne Klingl, Simone Jörs, Dawid Jaślan, Marco Keller, Sandra Prat Castro, Mane Mkhitaryan, Aicha Jeridi, Daria Briukhovetska, Barbara Spix, Anna Scotto Rosato, Ahmed Agami, Herbert B Schiller, Suhasini Rajan, Johann Schredelseker, Giorgio Fois, Manfred Frick, Sebastian Kobold, Margarethe Klein, Fabian Geisler, Jorge Garcia-Fortanet, Leon O Murphy, Franz Bracher, Christian Wahl-Schott, Thomas Gudermann, Alexander Dietrich, Martin Biel, Ali Önder Yildirim, Christian Grimm.
      In pulmonary fibrosis lung tissue is thickened and scarred, and the lungs become progressively stiffer and smaller, leading to low levels of blood oxygen and shortness of breath. Lung fibrosis is not curable and life expectancy is reduced. Fibrosis is characterized by an increased accumulation of extracellular matrix (ECM) proteins such as collagen and elastin. ECM proteins are degraded predominantly by matrix metalloproteinases (MMPs). Here, we show that the lysosomal cation channel TRPML1, which causes the lysosomal storage disorder mucolipidosis type IV (MLIV) when mutated or lost, regulates the levels of MMPs in the ECM of mouse airways, modulating exocytosis of MMP2, 8, 9, 12, and 19, which mediate collagen/elastin degradation. While TRPML1 loss reduces MMP levels in lung macrophage and fibroblast supernatants, small molecule activation of TRPML1 results in increased levels. MLIV mice display a fibrosis-like lung phenotype similar to the phenotype evoked by bleomycin. We thus identify TRPML1 as a regulator of MMP release in the lung with loss of TRPML1 resulting in lung fibrosis due to excessive extracellular collagen and elastin accumulation.
    Keywords:  Mcoln1; Pulmonary Fibrosis; TRPML; TRPML1; TRPML3
    DOI:  https://doi.org/10.1038/s44318-026-00712-4
  18. Nat Rev Mol Cell Biol. 2026 Feb 18.
    Subcellular localization as a driver of protein function.
    Alina Sigaeva, Charlotte Hutchings, Anthony Cesnik, Kathryn S Lilley, Emma Lundberg.
      Biological functions depend on the spatiotemporal distribution of proteins within cells. Key cellular activities such as signal transduction, metabolism, cell cycle and cell death are driven by the interactions of proteins that are localized in multiple cellular compartments. Such multilocalization can even allow protein with identical sequences to display multifunctionality, a phenomenon known as moonlighting. Despite its biological importance, the relationship between protein localization and function remains underexplored. In this Review, we discuss the known mechanisms of protein localization (including RNA transport, role of proteoforms and molecular interactions) and how subcellular localization controls protein function. Proper regulation of protein localization is crucial for specialized cell and tissue functions, including cell differentiation, polarization and the epithelial-mesenchymal transition. Protein mislocalization can also have important roles in pathological processes, such as in cancer, neurodegeneration and autoimmunity. We end with a discussion of current technological and conceptual challenges in the field of subcellular proteomics and spatial biology. Addressing these challenges will allow us to link the dynamic nature of protein localization and function across biological scales and contexts, with great impact on fundamental cell biology and clinical applications.
    DOI:  https://doi.org/10.1038/s41580-026-00947-3
  19. Nat Metab. 2026 Feb 16.
    A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.
    Xingxiu Pan, Subrata Munan, Austin L Zuckerman, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Nirajan Shrestha, Sara Violante, Justin R Cross, Russell P Goodman, Hardik Shah, Valentin Cracan.
      Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD⁺) are key metabolites of the Gro3P shuttle, which transfers reducing equivalents between the cytosol and mitochondria. Targeted activation of Gro3P biosynthesis has recently emerged as a promising strategy to alleviate reductive stress. However, because Gro3P constitutes the backbone of triglycerides, its accumulation can promote extensive lipogenesis. Here we show that a genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from the alga Chlamydomonas reinhardtii (CrGPDH) effectively operates both the alternative Gro3P shunt, which regenerates NAD⁺ while converting DHAP to Gro3P, and the glycerol shunt, which converts Gro3P to glycerol and inorganic phosphate, across transformed and primary mammalian cell cultures as well as mouse liver. CrGPDH expression supported proliferation of cancer cells under respiratory chain inhibition or hypoxia, as well as patient-derived fibroblasts with mitochondrial dysfunction. Moreover, CrGPDH decreased triglyceride levels in kidney cancer cell lines and reversed ethanol-induced triglyceride accumulation in mouse liver. Thus, CrGPDH represents a promising xenotopic tool to alleviate redox imbalance and associated impaired lipogenesis in conditions ranging from primary mitochondrial diseases to steatosis.
    DOI:  https://doi.org/10.1038/s42255-025-01450-3
  20. Nat Rev Drug Discov. 2026 Feb 20.
    The pancreatic cancer drug market.
    Pragati Tripathi, Laura Ramos García, Rachel M Webster.
      
    DOI:  https://doi.org/10.1038/d41573-026-00027-3
  21. Phys Rev E. 2026 Jan;113(1-1): 014407
    Geometry of disordered porous environments regulates cell migration.
    Laeschkir Würthner, Frederik Graw.
      Cell migration is a dynamic process that is of critical importance to various aspects of living organisms, including organogenesis, wound healing, and immune responses. Several external factors are known to influence and direct active cell movement, such as chemokine gradients and the composition and mechanical properties of the extracellular matrix (ECM). While progress has been made in elucidating some of the biochemical pathways that control cell migration, little is known about the impact of the porous structure of the ECM on active cell motion. Here, by combining computational modeling and theory, we reveal how porous environments, as represented by the ECM, determine cell migration dynamics. Simulating cell movement in a 3D cellular Potts model accounting for amoeboid-like cell shape dynamics, we show that cell migration within disordered porous environments is characterized by distinct transient motility regimes that deviate from persistent motion and are best described by the 'hopping' of cells between 'traps.' Using theory, we can show how these motility regimes and large-scale transport properties are linked to geometrical properties of the microstructure. Importantly, our analyses reveal that spatial heterogeneities in the porosity lead to nonhomogeneous cell distributions and effectively guide cell movement toward regions of low porosity, an effect which we term as porotaxis. Overall, our work reveals the porosity of the ECM as an important control parameter that shapes cell migration and cellular distribution, and provides a conceptual framework to relate experimentally observed cell motility modes to tissue structures and vice versa. This connection between geometry and cell motility could enhance our understanding of how structural elements shape cell migration and tissue organization in various conditions, such as chronic inflammation, immunity, and cancer.
    DOI:  https://doi.org/10.1103/hvtd-qwp1
  22. Methods Enzymol. 2026 ;pii: S0076-6879(25)00530-0. [Epub ahead of print]726 193-215
    Visualization of single-cell lipidomes with MALDI-MSI.
    Jean Andrea Maillat, Nika Goršek, Pavel Barahtjan, Giovanni D'Angelo.
      Lipids are central to cellular structure, metabolism, and signaling, and yet their distribution within and across cells is highly heterogeneous. Traditional bulk mass spectrometry masks this diversity, whereas single-cell lipidomics can uncover distinct lipid configurations that define cellular states and organize tissues. Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) has emerged as a powerful tool to probe lipid heterogeneity beyond bulk analyses. Here, we describe a workflow for single-cell lipidomics that integrates optimized matrix deposition, high-resolution acquisition, and optical co-registration. This approach enables label-free, spatially resolved detection of endogenous lipid species with cellular precision and minimal sample perturbation. Applied to cultured cells, the method uncovers pronounced cell-to-cell variability and reveals coherent lipid domains across neighboring cells in tissues. By providing a robust and scalable strategy for visualizing lipidomes at single-cell resolution, MALDI-MSI bridges the gap between lipid localization and metabolic diversity, advancing lipidomics toward the study of cellular identity, tissue organization, and disease mechanisms.
    Keywords:  MALDI-MSI; lipid heterogeneity; single-cell lipidomics; spatial metabolomics
    DOI:  https://doi.org/10.1016/bs.mie.2025.12.003
  23. bioRxiv. 2026 Feb 17. pii: 2026.02.05.703862. [Epub ahead of print]
    Structural basis of caveolin-driven membrane bending.
    Sarah M Connelly, Leon Bergner, Ajit Tiwari, Tyler S Brant, Samatha Medford, Siddanth Ramesh, Elizabeth D Tidwell, Youngki Yoo, Ke Xiao, J Gentry, Louise Chang, Bing Han, Padmini Rangamani, Milka Doktorova, Anne K Kenworthy, Shyamal Mosalaganti, Melanie D Ohi.
      Caveolins are monotopic membrane proteins essential for caveolae formation and play a key role in signaling and lipid regulation. Recent structural studies show that caveolins assemble into amphipathic disc-shaped oligomers with a central β-barrel, an architecture conserved across species and distinct from other membrane-remodeling proteins. These discs embed in the membrane by displacing lipids from a single leaflet, inducing membrane curvature. However, the mechanism of disc-driven bending remains unresolved. Using cryo-electron tomography, structure-guided mutagenesis, and mammalian cell studies, we show that evolutionarily distinct caveolins differ dramatically in their ability to induce membrane curvature despite sharing a conserved global architecture. Through computational and theoretical analyses, we further demonstrate that patterning of hydrophobic residues along the outer rim of the disc of human Caveolin-1 induces the deformation of the surrounding leaflet, which, in turn, dictates membrane bending. Finally, we determine a 4.1 A resolution structure of human Caveolin-1 within heterologous caveolae in situ, revealing that the disc adopts a funnel-like conformation, further shaping membrane architecture. Together, these findings reveal fundamental structural principles that empower caveolins to sculpt and remodel cellular membranes.
    DOI:  https://doi.org/10.64898/2026.02.05.703862
  24. Oncologist. 2026 Feb 17. pii: oyag040. [Epub ahead of print]
    MEK inhibitor-based genomically matched combinatorial targeted therapies in metastatic pancreatic adenocarcinoma with KRAS alterations.
    Elizabeth D Auckley, Stephanie Yohay, Grace Ying, Aniko Szabo, Jacquelyn Wittmann, Justin Grahl, Mohammed Aldakkak, Samih Z Thalji, Thomas McFall, Razelle Kurzrock, Ben George, Mandana Kamgar.
       INTRODUCTION: Pancreatic Ductal Adenocarcinoma (PDAC) is often caused by mutations in multiple genes including KRAS (activating the Ras-Raf-MEK-ERK pathway). This study evaluated the role of MEK inhibitor (MEKi)-based combinatorial targeted therapies in patients with PDAC. Methods. This is a retrospective/prospective observational, single institution study, including 29 patients with metastatic PDAC with KRAS alterations, treated with MEKi therapies between 2022-2024.
    RESULTS: Ten patients had KRAS G12R (34.5%), ten G12D (34.5%), and nine G12V (31%). Majority of patients received MEKi therapy as third-line and beyond (KRAS G12R/G12D/G12V 60%/50%/78%, respectively). Median overall survival from MEKi initiation for KRAS G12R/G12D/G12V was 8.2/5.1/4.7 months (P = 0.5), respectively, and median progression-free survival was 4.4/2.3/1.4 months (P = 0.11). Six (21%) patients discontinued at least one drug in the treatment combination due to toxicity.
    CONCLUSIONS: MEKi-based combinatorial therapies had modest disease control in patients with KRAS G12R, and minimal disease control in patients with KRAS G12D/V in the late-line setting.
    Keywords:  KRAS; MEK inhibitors; Pancreatic Ductal Adenocarcinoma; targeted therapy
    DOI:  https://doi.org/10.1093/oncolo/oyag040
  25. Cell. 2026 Feb 19. pii: S0092-8674(26)00056-5. [Epub ahead of print]
    A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
    Zhangchuan Xia, Xin Yang, Sviatlana N Samovich, Yulia Y Tyurina, Vladimir A Tyurin, Ning Kon, Jiankang Zhang, Xuejun Jiang, Brent R Stockwell, Jian Jin, Hülya Bayir, Valerian E Kagan, Wei Gu.
      Ferroptosis is a tumor-suppressive mechanism with therapeutic potential. While canonical ferroptosis is usually triggered by inducers, such as erastin and RSL-3, or by glutathione peroxidase (GPX)4 loss, how ferroptosis occurs naturally in vivo without these triggers has been unclear. Building on evidence that p53 can mediate ferroptosis as a natural tumor-suppressive pathway, we describe a noncanonical, in vivo ferroptosis driven by reactive oxygen species (ROS)-induced phosphatidic acid (PA) peroxidation that proceeds without inducers. We identify GPX1 as a key regulator of this ROS-induced ferroptosis by modulating PA peroxidation. GPX1's effects depend on OSBPL8, an endoplasmic reticulum (ER)-membrane-associated oxysterol-binding protein. ROS-driven lipid peroxidation accumulates at the ER before plasma membrane rupture and cell death; GPX1 is recruited to the ER via OSBPL8 and directly reduces oxidized PA. OSBPL8 and GPX1 are overexpressed in cancers; knockdown of either promotes ROS-induced ferroptosis and suppresses tumor growth. Our data link the GPX1-OSBPL8 axis to in vivo ferroptosis and tumor suppression.
    Keywords:  GPX1; GPX4; OSBPL8; ROS; cancer; ferroptosis; lipid peroxidation; p53; phosphatidic acid; phosphatidylethanolamine; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.01.009
  26. Cell Death Discov. 2026 Feb 19.
    Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
    Àngela Llop-Hernández, Sara Verdura, Júlia López, Begoña Martin-Castillo, Javier A Menendez, Elisabet Cuyàs.
      Mitochondria integrate senescence and apoptotic fates, yet it is unclear whether their ability to oxidize different fuels for energy production influences their vulnerability to senolytics in therapy-induced senescence (TIS). Using MitoPlates™ technology, we functionally mapped the mitophenotypes of TIS cancer cells by quantifying electron transport chain (ETC) flux from various NADH/FADH2 substrates. We then related these profiles to the responsiveness of TIS cancer cells to BCL-xL-targeting BH3 senolytics, as well as to inflammatory SASP signaling sensed by an NF-κB/miR-146a reporter. Mechanistically distinct senogenic stressors produced markedly different bioenergetic outputs and substrate diversity, establishing mitochondria as an emergent, stress-encoded property of TIS phenomena. Increased mitochondrial bioenergetic flexibility corresponded with senolytic permissiveness within each cell lineage. However, the magnitude of the senolytic response was largely limited by the pre-senescent bioenergetic configuration of the parental mitochondria, and baseline succinate oxidation served as a functional indicator of this inherited threshold. TIS SASPs were restricted by the secretome of the cell-of-origin, but only the miR146a-positive, fatty acid β-oxidation-related inflammatory SASP states were senolytically responsive. Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells.
    DOI:  https://doi.org/10.1038/s41420-026-02967-6
  27. J Lipid Res. 2026 Feb 13. pii: S0022-2275(26)00024-6. [Epub ahead of print] 100998
    DETERGENTS WITHOUT A DRAIN: THE EVOLUTIONARY LOGIC (AND LIABILITY) OF SPHINGOLIPIDS.
    Scott A Summers.
      Sphingolipids are evolutionarily conserved lipids that, I contend, emerged as a solution to a fundamental biochemical problem: cells require fatty acids, yet these molecules are potent detergents. In higher metazoans, a metabolic asymmetry amplifies this physical threat: unlike most macronutrients, fatty acids cannot be readily converted into non-lipid forms of biomass. Thus, when their supply exceeds energetic demand, they remain chemically committed lipids with the capacity to destabilize membranes and disrupt cellular organization. The emergence of sphingolipid metabolism offered an elegant solution to this challenge. By incorporating fatty acids into sphingolipids, cells both stabilize membranes to combat detergent stress and generate ceramide-dependent signaling programs that coordinate metabolic adaptation, remodeling, and, when necessary, cell elimination in response to lipid overload. In modern settings of chronic lipid surplus, most prominently obesity, this otherwise adaptive system becomes pathological. Across liver, adipose tissue, skeletal muscle, heart, pancreas, and kidney, excessive sphingolipid accumulation enforces metabolic inflexibility, impairs mitochondrial efficiency, and promotes cell dysfunction or loss, contributing to diabetes, steatohepatitis, heart failure, and kidney disease. Human studies consistently associate circulating ceramide species with cardiometabolic risk, while interventional studies in rodents demonstrate their causal roles in disease progression. Together, these findings position sphingolipids-much like cholesterol-as both early biomarkers and modifiable drivers of chronic disease, highlighting how an evolutionary solution becomes pathogenic in the setting of prolonged nutrient excess.
    DOI:  https://doi.org/10.1016/j.jlr.2026.100998
  28. Nat Cancer. 2026 Feb 20.
    Eythrocyte-anti-PD1 conjugates in persons with advanced solid tumors resistant to anti-PD1/PDL1: preclinical characterization and results of a phase 1 trial.
    Xiaoqian Nie, Yuehua Liu, Xingyun Yao, Qi Zhang, Yanjie Huang, Kurban Mattursun, Yuxiong Feng, Tingbo Liang, Liu Yang, Xiaofei Gao.
      Despite the clinical success of immune checkpoint blockade therapy, most persons do not benefit because of inadequate efficacy, primary or acquired resistance and/or immune-related toxicities. Here we developed an erythrocyte-antibody conjugate in which anti-PD1 antibodies are covalently linked to erythrocyte membranes (αPD1-Ery). Unlike conventional antibodies, αPD1-Ery accumulates in the spleen, where it remodels the immune landscape by expanding effector T cells and reducing immunosuppressive myeloid cells. These changes reprogram the tumor microenvironment and suppress tumor growth in syngeneic mouse models. We conducted a first-in-human, phase 1 clinical trial of αPD1-Ery monotherapy in persons with advanced cancers resistant to prior anti-PD1/PDL1 therapy ( NCT06026605 ). The primary objective was safety; secondary objectives included efficacy, pharmacokinetics, pharmacodynamics and immunogenicity. A total of 14 participants were enrolled, with 7 receiving 2 × 1011 cells and 7 receiving 3 × 1011 cells. Repeated administration resulted in no dose-limiting toxicities or treatment-related adverse events of grade >3. The objective response rate was 42.9%, including 1 complete response and 5 partial responses; disease control rate was 78.6%. Notably, αPD1-Ery rapidly reduced circulating immunosuppressive myeloid cells, consistent with preclinical observations. The study met its prespecified primary and secondary endpoints. These findings support spleen-targeted PD1 blockade by erythrocyte-antibody conjugates as a potential strategy for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-026-01125-2
  29. Mol Cell Proteomics. 2026 Feb 17. pii: S1535-9476(26)00026-5. [Epub ahead of print] 101530
    pmultiqc: An open-source, lightweight, and metadata-oriented QC reporting library for MS proteomics.
    Qi-Xuan Yue, Chengxin Dai, Selvakumar Kamatchinathan, Chakradhar Bandla, Henry Webel, Asier Larrea, Wout Bittremieux, Julian Uszkoreit, Tom David Müller, Jinqiu Xiao, Juergen Cox, Fengchao Yu, Philip Ewels, Vadim Demichev, Oliver Kohlbacher, Timo Sachsenberg, Chris Bielow, Mingze Bai, Yasset Perez-Riverol.
      The increasing scale and complexity of proteomics data demand robust, scalable, and interpretable quality control (QC) frameworks to ensure data reliability and reproducibility. Here, we present pmultiqc, an open-source Python package that standardizes and generates web-based QC reports across multiple proteomics data analysis platforms. Built on top of the widely adopted MultiQC framework, pmultiqc offers specialized modules tailored to mass spectrometry workflows, with full initial support for quantms, DIA-NN, MaxQuant/MaxDIA, FragPipe, and mzIdentML/mzML-based pipelines. The package computes a wide range of QC metrics, including raw intensity distributions, identification rates, retention time consistency, and missing value patterns, and presents them in interactive, publication-ready reports. By leveraging sample metadata in the SDRF format, pmultiqc enables metadata-aware QC and introduces, for the first time in proteomics, QC reports and metrics guided by standardized sample metadata. Its modular architecture allows easy extension to new workflows and formats. Alongside comprehensive documentation and examples for running pmultiqc locally or integrated into existing workflows, we offer a cloud-based service that enables users to generate QC reports from their own data or public PRIDE datasets.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101530
  30. Methods Enzymol. 2026 ;pii: S0076-6879(25)00486-0. [Epub ahead of print]726 85-104
    Alkyne lipids as tracers of lipid metabolism.
    Christoph Thiele.
      The high complexity of cellular lipidomes and of the underlying metabolic pathways requires powerful labeling and detection systems for systematic lipid tracing experiments. Alkyne fatty acids are tracers with favorable biological properties very similar to unlabeled natural counterparts. We have developed a labeling and detection system based on alkyne lipid tracers and specialized reporter molecules that confer high specificity and sensitivity to labeled metabolites. Tracers are added to living cells and metabolites are extracted in pulse-chase setups to achieve time resolution. Copper(I)-dependent click reaction between extracted lipids and the C171 or C175 reporter molecules is followed by mass spectrometry analysis. The reporter carries a positive charge leading to improved ionization and increased sensitivity. Uniform and predictable neutral loss-type fragmentation in tandem mass spectrometry leads to reliable identification and quantification of labeled metabolites. Parallel multi-labeling with several precursors, combined with multiplexed analysis enables efficient high-content tracing. This chapter introduces the basic concepts and a step-by-step protocol with detailed explanation of key procedures to obtain optimal results.
    Keywords:  Click reaction; Lipid metabolism; Mass spectrometry; Reporter molecule
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.005
  31. J Lipid Res. 2026 Feb 13. pii: S0022-2275(26)00027-1. [Epub ahead of print] 101001
    Lipidation as a post-translational code for protein liquid-liquid phase separation.
    Soodabeh Abbasi Sani, Agnieszka Chytła, Martin Sztacho.
      Liquid-liquid phase separation has emerged as a central organizing mechanism that drives the formation of biomolecular condensates and enables cells to spatially and temporally coordinate metabolism, signaling, and gene expression. While the influence of post-translational modifications such as phosphorylation and ubiquitination on condensate behavior is well established, the contribution of lipidation, the covalent attachment of lipid moieties to proteins, to these processes has received far less attention. Lipidation dictates protein hydrophobicity, membrane affinity, and subcellular distribution, yet how these parameters influence LLPS and thereby modulate condensate dynamics remains unclear. We propose that lipidation operates as a molecular code that integrates membrane association with phase separation, thereby tuning the assembly, composition, and thus functional output of condensates. Extending this concept beyond classical membrane systems, we further suggest that nuclear phosphoinositides, particularly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) may act as an unconventional lipid modifier that structures membrane-less nuclear compartments through a process termed PIPoylation. Drawing on recent findings, we outline how canonical covalent lipidations, including palmitoylation, myristoylation, prenylation, and phospholipidation, govern membrane nanodomain organization, autophagy, and nuclear condensate architecture. We discuss how covalent lipidation influences condensate wetting, membrane curvature, and lipid-protein demixing, and how PI(4,5)P2 metabolism links chromatin remodeling with transcriptional control via LLPS. Together, these mechanisms underscore lipidation as a crucial regulator of condensate-membrane communication across cellular compartments.
    Keywords:  biomolecular condensates; cell signaling; lipid rafts; membrane organization; phosphoinositides; phospholipids; post-translational modifications; transcription
    DOI:  https://doi.org/10.1016/j.jlr.2026.101001
  32. Adv Sci (Weinh). 2026 Feb 17. e19792
    Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
    Bin-Hsu Mao, Bo-Kai Su, Ying-Jan Wang, Ting-Yuan Tu.
      Metastatic invasiveness emerges from coordinated intrinsic programs and microenvironmental cues that converge on mitochondrial quality control (MQC). Here, we use "context" to denote stage- and site-aware constellations of tumor-intrinsic states (e.g., mtROS tone, mtDNA integrity, epigenetic wiring, cellular stiffness, oncogenic mutations) and extrinsic landscapes (oxygen-nutrient availability, ECM mechanics, stromal/inflammatory signals). These axes jointly shape mitochondrial adaptation by tuning bioenergetics, redox balance, metabolic plasticity, fission-fusion dynamics, mechanosensitive hubs, and Ca2 + homeostasis. As pressures intensify, mitochondrial vulnerabilities-such as mtDNA compromise and mtUPR activation-signal the engagement of mitophagy to preserve organelle fitness under stress. Through these coupled changes in mitochondrial performance and stress responses, context governs EMT/MET plasticity and transitions across migratory, invasive, and proliferative states. Mechanistically, ubiquitin conjugation, via E3 ligases and deubiquitinases, serves as an integrating conduit that links mitochondrial remodeling and mitophagy to cytoskeletal reprogramming and invasive behavior. This ubiquitin-mitochondria interface therefore represents a coherent therapeutic entry point; translational strategies including PROTAC-enabled targeting and selective E3/DUB or mitophagy-pathway modulators may rebalance pathological ubiquitin signaling, restore mitochondrial homeostasis, and constrain tumor dissemination.
    Keywords:  EMT–MET plasticity; extracellular matrix mechanics; hypoxia and nutrient deprivation; mitochondrial ROS; mitochondrial dynamics; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202519792
  33. Methods Enzymol. 2026 ;pii: S0076-6879(25)00491-4. [Epub ahead of print]726 289-319
    Metabolic labeling of glycerophospholipids.
    Robert J Maraski, Christelle F Ancajas, Jinchao Lou, Michael D Best.
      The approach of metabolic labeling provides an invaluable tool for elucidating previously unknown and poorly understood metabolic processes within cells. By introducing clickable versions of substrates into cells, the products of these biomolecule mimics can be conveniently tracked via post-derivatization of the clickable tag with a variety of reporter groups. Here, we will describe lipid metabolic labeling as an invaluable approach for interrogating lipid metabolic pathways, which can yield crucial information regarding complex lipid biosynthesis and trafficking networks that can open new therapeutic targets involving downstream natural products. In this chapter, we present detailed experimental procedures for the development of clickable serine probes for the labeling of phosphatidylserine (PS) and other lipids, including probe design and synthesis as well as analysis of biological incorporation via confocal microscopy, thin-layer chromatography (TLC), and liquid chromatography mass spectrometry (LCMS). This strategy provides a powerful approach for interrogating lipid biosynthetic pathways centered around PS.
    Keywords:  Click chemistry; Fluorescence microscopy; Lipids; Membranes; Metabolic labeling; Phosphatidylserine; Phospholipids
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.010
  34. Cell Metab. 2026 Feb 18. pii: S1550-4131(26)00015-X. [Epub ahead of print]
    Lipid droplet-induced T cell death sustains autoimmune tissue inflammation.
    Jitendra Kumar, Yoshinori Takashima, Jose Morales, Brandon Wong, Lina Werner, Isabel N Goronzy, Selene Rubino, Robert T Trousdale, Gerald J Berry, Jörg J Goronzy, Cornelia M Weyand.
      Autoimmunity leading to rheumatoid arthritis (RA) involves CD4+ T cell recruitment into synovial tissue. However, metabolic conditions supporting the survival and pro-inflammatory effector functions of these tissue-invading T cells remain poorly understood. Lipidomic analysis identified the inflamed synovium as a lipid-rich environment. In functional studies, administration of the free fatty acid oleic acid exacerbated synovitis. Tissue-invading CD4+ T cells responded to fatty acid with rapid cell lysis, releasing cytoplasmic and nuclear content into the extracellular space. This T cell lytic death required sequestration of the pore-forming molecule gasdermin D and the acyltransferase zDHHC5 to lipid droplets, which translocated to the plasma membrane to trigger membrane rupture and pyroptotic cell death. Targeting lipid droplet formation in CD4+ T cells through perilipin-2 knockdown or inhibiting gasdermin activation by blocking protein acylation proved highly effective in suppressing synovitis. Thus, autoimmune CD4+ T cells lack metabolic resilience, are primed to undergo pyroptosis in lipid-rich environments, and deliver pro-inflammatory cargo to surrounding tissue.
    Keywords:  T cell; autoimmune disease; gasdermin D; inflammation; lipid droplet; protein S-acylation; pyroptosis
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.014
  35. Sci Adv. 2026 Feb 20. 12(8): eadx7501
    Evidence that extra copies of chromosome 1q play a role in the early phases of pancreatic neoplasia.
    Christopher Douville, Jeeun Parksong, Marco Dal Molin, Sarah Graham, Patricia T Greipp, Ryan Knudson, Samuel Curtis, Yuxuan Wang, Lisa Dobbyn, Maria Popoli, Janine Ptak, Natalie Silliman, Katharine Romans, Christine A Iacobuzio-Donahue, Alvin P Makoohon-Moore, Anne Marie Lennon, Michael Goggins, Ralph H Hruban, Ashley Kiemen, Chetan Bettegowda, Kenneth W Kinzler, Nickolas Papadopoulos, Laura D Wood, Bert Vogelstein.
      We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2, genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.
    DOI:  https://doi.org/10.1126/sciadv.adx7501
  36. Methods Enzymol. 2026 ;pii: S0076-6879(25)00521-X. [Epub ahead of print]726 181-191
    Non-invasive imaging of phosphoinositides with genetically encoded lipid biosensors.
    Michael Worcester, Magdalene Motter, Gerald R V Hammond.
      The localization and metabolism of lipids are difficult to dynamically resolve. Whereas immunofluorescence techniques rely on fixing cells and subsequent postmortem examination, and the employment of fluorescent lipid analogs in turn depends on approximative probes, genetically encoded lipid biosensors are not invasive and report on endogenous targets in living cells. Here we outline a protocol for imaging PI(4,5)P2 localization in live HEK293A cells by expression of the genetically encoded lipid biosensor PH-PLCδ1. The protocol is presented as having two branching paths, with the first detailing how to overexpress the biosensor for confocal microscopy. The second path describes expression of the biosensor at single molecule levels for subsequent TIRF microscopy.
    Keywords:  Confocal microscopy; Genetically encoded lipid biosensors; PI(4,5)P2; Phosphoinositides; Plasma membrane; TIRF microscopy
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.017
  37. Nat Mater. 2026 Feb 20.
    Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties.
    Jasmin Kaivola, Karolina Punovuori, Megan R Chastney, Hind Abdo, Gautier Follain, Mathilde Mathieu, Omkar Joshi, Yekaterina A Miroshnikova, Fabian Krautgasser, Jasmin Di Franco, James R W Conway, Sofia Held, Fabien Bertillot, Jaana Hagström, Antti Mäkitie, Heikki Irjala, Sami Ventelä, Hellyeh Hamidi, Giorgio Scita, Roberto Cerbino, Sara A Wickström, Johanna Ivaska.
      Increased extracellular matrix deposition and stiffness promotes solid tumour progression. Yet, the precise mechanotransduction pathways, especially in less-studied mechanically responsive cancers, remain poorly understood. Here we address this gap using patient-derived tumour cells from early (mobile, T1) and advanced (immobile, T3) stages of vocal fold cancer, the most common squamous cell carcinoma severely impacting the voice box. We reveal that vocal fold cancer progression is linked to cell surface receptor heterogeneity, a loss of laminin-binding integrins in cell-cell junctions and a flocking mode of collective cell motility. Mimicking the physiological movement of healthy vocal fold tissue with stretching or vibrations decreases oncogenic β-catenin and Yes-associated protein (YAP) nuclear levels in vocal fold cancer. Multiplex immunohistochemistry of vocal fold cancer tumours shows a correlation between the extracellular matrix composition, nuclear YAP and patient survival, concordant with vocal fold cancer sensitivity to oncogenic YAP-TEAD Hippo pathway inhibitors both in vitro and in vivo. Overall, our findings suggest that vocal fold cancer is a mechanically sensitive malignancy, and that the restoration of tumour mechanophenotype or YAP/TAZ targeting represents a tractable anti-oncogenic therapeutic avenue for vocal fold cancer.
    DOI:  https://doi.org/10.1038/s41563-025-02473-7
  38. Mol Biol Cell. 2026 Feb 18. mbcE25070362
    Membrane composition-dependent patterning of Rho and F-actin in an artificial cell cortex.
    Gregory J Schwarz, Joanna R Suber, Devika Andhare, Michael J Ragusa, Jennifer Landino.
      Cortical excitability, a phenomenon in which the cell cortex is dynamically patterned with waves of F-actin assembly, has been described in a variety of model systems, including embryos of mammals, flies, frogs and echinoderms, as well as a variety of cultured cells. While the cortical F-actin network is closely linked with the plasma membrane, it is not known if membrane composition or fluidity regulates dynamic cytokinetic patterning. Phospholipids partition within the plasma membrane during cytokinesis, and phosphoinositides play a key regulatory role in other excitable systems, suggesting a role for membrane-dependent regulation of cytokinetic patterning. Here we use an artificial cell cortex comprised of Xenopus laevis egg extract and supported lipid bilayers (SLBs) to show that membrane composition regulates self-organized cortical patterning. We find that manipulating the levels of candidate lipids, including phosphatidylinositol 4,5-bisphosphate, phosphatidylethanolamine, sphingomyelin and cholesterol, changes the dynamics of traveling waves and standing oscillations of active Rho and F-actin, as well as the kinetics of Rho activation and F-actin assembly on SLBs. Our findings demonstrate that membrane composition regulates the assembly of cortical F-actin, as well as emergent active Rho and F-actin patterning. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-07-0362
  39. Nat Chem Biol. 2026 Feb 17.
    A two-step clockwork mechanism opens a proteo-lipidic pore in PIEZO2.
    Shu Li, Tharaka Wijerathne, Aashish Bhatt, Wenjuan Jiang, Jerome Lacroix, Wei Han, Yun Lyna Luo.
      Mechanosensitive PIEZO channels are thought to open via tension-induced flattening of peripheral transmembrane arm domains, yet the structural basis of this activation remains unclear. Here, by leveraging hybrid-resolution molecular dynamics simulations, we uncover how large-scale PIEZO2 arm movements funnel into subtle gating motions in the central pore under physiological tension. Arm flattening correlates with anticlockwise rotation of the pore relative to the arms and with clockwise twisting of inner pore helices. These clockwork motions open the pore in a two-step fashion, yielding a fully conducting state and a stable subconducting state populated at a low tension, which was detected electrophysiologically. The fully open PIEZO2 pore is walled by both lipids and amino acids and recapitulates minimal pore size, conductance, ion selectivity and outward rectification of chloride currents measured electrophysiologically. These findings provide structural insights into PIEZO2 gating and demonstrate hybrid-resolution molecular dynamics as a powerful approach to study large-scale membrane protein dynamics and guide drug discovery.
    DOI:  https://doi.org/10.1038/s41589-026-02147-8
  40. Methods Enzymol. 2026 ;pii: S0076-6879(25)00523-3. [Epub ahead of print]726 253-267
    Strategies to minimize artificial lipid oxidation in mass spectrometry based epilipidomics analysis.
    Sider Penkov, Gabriele Lombardi Bendoula, Maria Fedorova.
      (Per)oxidized lipids represent a well-studied component of the epilipidome, a subset of the native lipidome formed through both enzymatic and non-enzymatic lipid oxidation. Given their diverse biological roles, including cellular signalling, regulation of immune responses, and modulation of cell death pathways, accurate detection of lipid peroxidation products is essential. Mass spectrometry-based approaches have become the method of choice for the sensitive, multiplexed detection and structural characterization of oxidized lipids across a variety of biological samples. However, the structural features of lipids, particularly the presence of acyl chains containing multiple double bonds, render them susceptible not only to endogenous oxidation but also to artificial oxidation during sample preparation prior to analysis. Consequently, special care must be taken throughout sample collection, storage, and lipid extraction to minimize artefacts arising from lipid autoxidation. Here, we describe protocols developed in our laboratory over recent years aimed at preventing artificial lipid oxidation during sample preparation, with examples spanning biological materials derived from cell culture, animal and human tissue biopsies, and biofluids. Finally, we propose internal quality control procedures to assess the effectiveness of these measures in preventing lipid autoxidation.
    Keywords:  Autoxidation; Epilipidomics; Lipid peroxidation; Quality assurance; Sample preparation
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.019
  41. Cell. 2026 Feb 18. pii: S0092-8674(25)01499-0. [Epub ahead of print]
    Tuning the sensitivity of mechanosensory receptors through histidine scanning.
    Yuanhao Wang, Yuhan Wang, Wenjie Yuan, Mingyu Fan, Xiaojing Wang, Anhui Wang, Yanling Bao, Yajing Zhang, Jia Chi Tan, Jianglai Wang, Junshuang Liu, Tianqi Huang, Zixuan Han, Biling Pei, Lijuan Chen, Zhengxu Ren, Xueqing Wang, Lanxin Hu, Siqi Wu, Mengke Pang, Sifan Wang, Zihuan Yang, Jiaze Li, Delian Huang, Shuai Shao, Huairui Yuan, Ling Wu, Yinnian Feng, Penghui Zhou, Guohui Li, Bo Sun, Chenqi Xu, Nicholas R J Gascoigne, Xiang Zhao.
      T cell receptor (TCR)-T cell therapy is effective for solid tumors, yet identifying potent, specific TCRs for tumor antigens is challenging. Conventional affinity maturation may cause fatal off-target toxicity. Catch bonds play a crucial role in mechanosensory receptor signaling, including the TCR, but their formation and potential to mitigate the challenges of TCR-T remain unclear. Here, we demonstrate that histidine scanning can identify TCR hotspots capable of forming additional catch bonds, which can be randomized to create TCR libraries for screening low-affinity, higher-potency variants. Mechanistically, histidine facilitates the formation of hydrogen bonds and salt bridges and fortifies the intracellular signaling cascade. Using this approach, we engineered different TCRs specific for various antigens, without off-target toxicity or on-target toxicity. Our findings introduce a universal method of engineering low-affinity, high-potency TCRs for safe TCR-T cell therapy, without requiring the structure for designing TCR libraries. Additionally, histidine scanning can be broadly applied to other mechanosensory ligand-receptor systems.
    Keywords:  FcR; MAGE-A3; Notch; TAK1; TCR; TCR-T cell therapy; WT-1; cancer immunotherapy; catch bond; histidine scanning
    DOI:  https://doi.org/10.1016/j.cell.2025.12.050
  42. Adv Sci (Weinh). 2026 Feb 17. e02239
    CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis.
    Hong Zhou, Wan Fu, Shizuo Liu, Zili Zhang, Hanyan Luo, Qing Zhong.
      Ferroptosis is a type of regulated cell death characterized by the accumulation of lipid peroxides that damage cell membranes specifically. Mitochondrial swelling and dysfunction are hallmarks of ferroptosis; however, what causes mitochondrial swelling and the consequences of mitochondrial swelling in ferroptotic signal transduction remain poorly understood. Our study found that mitochondrial permeability transition pore (mPTP) opening is essential for mitochondrial swelling and ferroptosis activation. During ferroptosis, oxidized mitochondrial DNAs (mtDNAs) are released through the mPTP. These oxidized mtDNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, promoting ferroptosis through activating ferrotinophagy. Consistently, inhibition of mtDNA-repair enhances cellular sensitivity to ferroptosis and therefore synergizes with ferroptosis inducer in suppressing tumorigenesis in mouse xenograft tumor models. This study provides a fundamental understanding of how mPTP engages in ferroptosis by releasing mitochondrial DNAs as crucial messengers to activate ferroptotic signaling.
    Keywords:  cGAS‐STING; ferroptosis; mPTP; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/advs.202502239
  43. Bioinformatics. 2026 Feb 15. pii: btag073. [Epub ahead of print]
    InSituPy: A framework for histology-guided, multi-sample analysis of single-cell spatial omics data.
    Johannes Wirth, Anna Chernysheva, Birthe Lemke, Isabel Giray, Katja Steiger.
       MOTIVATION: Single-cell spatial omics data provides unprecedented insights into disease states. Comprehensive analysis of such data requires frameworks that integrate diverse modalities and enable joint processing of multiple datasets and corresponding metadata.
    RESULTS: To address these challenges, we introduce InSituPy, a versatile and scalable framework for analyzing spatial omics data from the multi-sample level down to the cellular and subcellular level. Its modular data structure organizes all relevant data modalities per sample and links them to their corresponding metadata, enabling scalable analysis of large patient cohorts using spatial omics technologies. Interactive visualization tools within InSituPy enable seamless integration of histopathological expertise, promoting collaborative hypothesis generation in translational research. Additionally, InSituPy includes built-in analytical algorithms and interfaces with external tools, establishing a standardized workflow for multi-sample spatial omics data analysis.
    AVAILABILITY: The Python packages InSituPy is publicly available on GitHub (https://github.com/SpatialPathology/InSituPy) and PyPi (https://pypi.org/project/insitupy-spatial/), and archived on Zenodo (DOI: 10.5281/zenodo.18459471). Tutorials and documentation for InSituPy are available at https://insitupy.readthedocs.io/. All code to replicate the results shown in this manuscript can be found in the GitHub repository. Scripts to connect QuPath and InSituPy can be found at https://github.com/SpatialPathology/InSituPy-QuPath. All data required to complete the tutorials is publicly available, and functions to download the data have been implemented. A Zulip community chat for user support and discussion is accessible at https://insitupy.zulipchat.com.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag073
  44. Gastroenterology. 2026 Feb 13. pii: S0016-5085(26)00102-2. [Epub ahead of print]
    STING ablation in T cells is required for the efficacy of STING agonists in CAR-T cell immunotherapy of pancreatic cancer.
    Ignazio Piseddu, Rebekka Endres, Fabian Lanzl, Linda Hammann, Marleen Bérouti, Matthias Thaler, Lisa Fahr, Hannah Fischer, Varvara Varlamova, Jan Gärtig, Daniel Nixdorf, Patrick Layritz, Charlotte Marx, Christine Hörth, Catharina Witte, Alpay Bulut, David Illig, Anne Marie Senz, Lesca Holdt, Ivonne Regel, Adrian Gottschlich, Marion Subklewe, Julia Mayerle, David Anz, Sebastian Kobold, Andreas Linder, Veit Hornung.
       BACKGROUND & AIMS: Chimeric antigen receptor (CAR) T cells have shown great potential in hematological cancers, but lack efficacy in solid tumors, highlighting the need for novel strategies. STING activation was shown to inflame the tumor microenvironment, but combination of STING agonists and CAR-T cells might be limited by detrimental outcomes of T cell-intrinsic STING activation. In this study, we evaluated the potential of combining STING agonists and CAR-T cells in the context of pancreatic cancer METHODS: We assessed the synergy of CRISPR-Cas9-edited CAR-T cells and the STING agonist diABZI within a T cell exhaustion model in vitro and both xenograft and syngeneic mouse models in vivo.
    RESULTS: Combination of STING-ablated CAR-T cells and diABZI resulted in enhanced cancer cell killing, increased CAR-T cell proliferation, reduced exhaustion and expansion of an effector-memory phenotype in vitro. Mechanistically, superior CAR-T cell functionality required genetic ablation of STING in CAR-T cells and was dependent on cancer cell-intrinsic STING signaling upon STING-agonistic treatment. Moreover, we identified a synergistic feedback loop comprising the T cell-secreted cytokines IFN-γ and TNF, which prime STING signaling within cancer cells, thereby potentiating the outcomes of cancer cell-intrinsic STING activation in inducing ameliorated CAR-T cell states. Ultimately, we could demonstrate that combination of STINGKO CAR-T cells and diABZI was able to provide enhanced tumor control in both xenograft and syngeneic mouse models. This was accompanied by increased intratumoral CAR-T cell numbers and reprogramming of the tumor microenvironment in vivo.
    CONCLUSION: Our findings suggest that STINGKO CAR-T cells stand to benefit from STING agonists to improve CAR-T cell therapy for immune-deprived cancers such as pancreatic cancer.
    Keywords:  CAR-T cells; CRISPR-Cas9; PDAC; STING
    DOI:  https://doi.org/10.1053/j.gastro.2026.01.031
  45. Anal Chem. 2026 Feb 17.
    A Membrane-Impermeable Near-Infrared Probe Enables High-Fidelity Tracking of Foam Cell Progression.
    Tian Li, Chuixi Kong, Jiaqi Zuo, Penglei Wu, He Zhao, Kaiyi Jiang, Jin Zhou, Tiejun Zhao, Hui Feng, Zhigang Jin, Zhaosheng Qian.
      Foam cell formation is a key pathological event in atherosclerosis, which can be used as an early diagnosis and drug selection platform for atherosclerotic disease. Current methods are hindered by an inability to distinguish pathological lipid aggregates in foam cells from normal lipid droplets in healthy macrophages in a live-cell context. Herein, we developed and synthesized a membrane-impermeable, near-infrared fluorescent probe named FMNIR-DBO for high-fidelity imaging of foam cell formation. The membrane impermeability was achieved by incorporating a charged, rigid moiety into a near-infrared D-π-A fluorophore, thereby enabling long-term anchoring to the plasma membrane in live cells. This probe uniquely exploits the loss of plasma membrane integrity that occurs as macrophages transform to foam cells. Consequently, FMNIR-DBO remains extracellular to healthy cells but selectively enters foam cells to illuminate pathological lipid aggregates, thereby eliminating interference from normal lipid droplets. This strategy enables rapid, dynamic imaging of lipid accumulation in living foam cells within 6 h, a 75% reduction in time compared to conventional Oil Red O staining. Furthermore, FMNIR-DBO was used to evaluate the cellular-level effects of ethanol on foam cell formation, providing robust evidence to support its role in excess-alcohol-induced atherosclerotic disease progression.
    DOI:  https://doi.org/10.1021/acs.analchem.5c07250
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒22 at 18:49.