bims-nakice Biomed News
on Natural killer cells
Issue of 2026–08–30
eleven papers selected by
Santosh Phuyal, Oslo Universitetssykehus
  1. Assessment of Natural Killer Cell Serial Degranulation.
  2. Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces.
  3. 3D chemotaxis chip for investigating natural killer cell migration mechanisms.
  4. A Microfluidic Platform for Studying Roles of Mechanical Compression in Tumor-Immune Cell Interactions in a 3D Extracellular Matrix.
  5. IL-15 boosts mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting.
  6. A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.
  7. The long and winding road: On the endoplasmic reticulum of Plasmodium and implications for pathogenesis.
  8. Cell-Type-Tailored Hydrogels for Adoptive Cell Therapy in Cancer.
  9. Inhibition of the lipocalin-2-phosphatidylserine axis restores natural killer cell immune surveillance.
  10. Automated Deep Learning Protocol for Quantifying Cell Viability in Live/Dead Fluorescence Microscopy.
  11. A biphasic hydrogel prevents glioblastoma recurrence by activating an EZH2-NeuroD1-SRCIN1 neuronal conversion axis.
  1. Curr Protoc. 2026 Aug;6(8): e70452
    Assessment of Natural Killer Cell Serial Degranulation.
    Jens A Niemann, Carsten Watzl.
      Natural killer (NK) cells have been shown to be heterogeneous and to differ in their ability to kill target cells: although some NK cells show little cytotoxic activity, others sequentially kill multiple targets. The latter are called serial killers, and they perform this activity mainly via the release of cytotoxic granules. During this degranulation process, CD107a is exposed at the NK cell's surface. By staining this extracellular CD107a in a sequential manner, the ability of NK cells to serially degranulate while in co-culture with target cells can be analyzed. Here we describe a protocol for the detection and characterization of serial degranulating human NK cells. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Natural killer cell serial degranulation assay.
    Keywords:  cytotoxicity; degranulation; natural killer cells; serial killing
    DOI:  https://doi.org/10.1002/cpz1.70452
  2. Sci Adv. 2026 Aug 28. 12(35): eaeb8946
    Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces.
    Rong Ma, K Christopher Garcia, Bianxiao Cui, Markus W Covert.
      Natural killer (NK) cells eliminate target cells through antibody-dependent cell-mediated cytotoxicity (ADCC), initiated by CD16a (FcγRIIIa) recognizing the Fc region of antibodies bound to the target cell surface. While the recognition is considered to be driven by CD16a-Fc binding avidity, it fails to explain why Fc multimers inhibit ADCC in solution rather than trigger it. Here, we reveal that CD16a transduces piconewton forces and acts as a mechanosensor to facilitate NK activation. We demonstrate that CD16a force and the actin foci formation associated with it are essential for the phosphorylation of mechanosensitive adaptor Cas-L and signaling adaptor LAT (linker of activation of T cells), reshaping NK cell cytoskeletal dynamics and signaling. Our findings show that NK activation is an intricate process that integrates both biochemical and biophysical information and provide fresh mechanistic insight for immunoengineering.
    DOI:  https://doi.org/10.1126/sciadv.aeb8946
  3. Front Immunol. 2026 ;17 1762203
    3D chemotaxis chip for investigating natural killer cell migration mechanisms.
    Madison N Temples, Suzanne Lightsey, Tiffany Conklin, Rylee S Newport, Edward A Phelps, Blanka Sharma.
       Introduction: Natural killer (NK) cells are a promising tool for cancer immunotherapy, as they can rapidly recognize and kill cancer cells without prior knowledge of tumor-specific antigens while leaving healthy cells unharmed. However, a major challenge in NK cell-based therapies is their inadequate infiltration and function within solid tumors. Advancements in NK cell therapies for solid malignancies require an understanding of the various factors that influence NK cell migration to and within the tumor microenvironment.
    Methods: In this study, we developed a chemotaxis chip with a tunable 3D hydrogel that enabled the spatiotemporal analysis of NK cell migration. Through live-cell imaging and cell-tracking analysis, we quantitatively assessed NK cell migration in engineered hydrogels in real time. This platform enabled precise control over matrix composition and physical properties, allowing systematic interrogation of microenvironmental features that regulate NK cell migration.
    Results: Our findings revealed that NK cells rely heavily on proteasedependent infiltration but can leverage alternative mechanisms for faster migration, and that the inclusion of hyaluronic acid, a tumorrelated extracellular matrix component, promotes NK cell migration in 3D.
    Discussion: This study established an adaptable hydrogel-based platform for studying immune cell migration in defined 3D environments, providing foundational tools for future mechanistic and translational investigations.
    Keywords:  biomaterials; cancer immunotherapy; cell migration; natural killer cells; three-dimensional; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1762203
  4. J Vis Exp. 2026 Aug 28.
    A Microfluidic Platform for Studying Roles of Mechanical Compression in Tumor-Immune Cell Interactions in a 3D Extracellular Matrix.
    Faith Muriuki, Kaitlyn Roach, Young Joon Suh, Mrinal Pandey, Brian C H Cheung, Jeffrey E Segall, Mingming Wu.
      Mechanical forces significantly influence the ability of immune cells to kill tumor cells in the context of cell-based immunotherapy. To kill tumor cells, immune cells must exert forces on the target cell and form an immune synapse, through which cytotoxic molecules -including granzyme B-are delivered. Despite their importance, how mechanical cues can be leveraged to enhance immune-mediated killing remains poorly understood. This knowledge gap is partly due to the lack of tools capable of providing well-controlled mechanical stress to cell cultures in a physiologically realistic environment. Here, we describe a microfluidic compression device that can apply static or dynamic compression to tumor spheroids embedded in extracellular matrix (ECM) while enabling real-time imaging of tumor-immune interactions via optical microscopy. The microfluidic platform consists of 12 compartments (6 control and 6 functional). Each compartment contains a cell chamber positioned directly beneath the pressure control unit. Spheroids embedded in ECM are placed within the cell chamber. Using this platform, we investigated the killing efficiency of Natural Killer (NK) cells against breast tumor spheroids (MCF-7) under defined mechanical compression. The results showed that NK cells remained the primary drivers of tumor spheriods death regrardless of mechanical compression in 1.5 mg/mL collagen. Therefore, suggesting that NK cells can maintain their anti-tumor activity under compressive stress. These findings demonstrate the utility of this platform for investigating the role of mechanical forces in tumor-immune interactions. Ongoing studies are identifying the molecular mechanisms that allow immune cells to adapt to compressive stress. Insights gained from these studies may reveal a promising therapeutic avenue.
    DOI:  https://doi.org/10.3791/72929
  5. Mol Ther Oncol. 2026 Sep 17. 34(3): 201316
    IL-15 boosts mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting.
    Laura Gehrcken, Jasper Ott, Astrid Van den Eynde, Ho Wa Lau, Dana Liu, Christophe Hermans, Tias Verhezen, Stefanie Peeters, Carole Faghel, Philippe Joye, Gils Roex, Diana Campillo-Davo, Eva Lion, Filipe Elvas, Senada Koljenovic, Jorrit De Waele, Vera Hartman, Geert Roeyen, Hans Prenen, Filip Lardon, Christophe Deben, Evelien Smits, Jonas Van Audenaerde.
      Chimeric antigen receptor (CAR) therapies have shown great success in hematological malignancies but remain largely ineffective against solid tumors such as pancreatic ductal adenocarcinoma (PDAC). A key obstacle among various aspects, is the dense stromal barrier formed by cancer-associated fibroblasts (CAFs), providing a rationale for simultaneously targeting stroma and tumor cells. Using immunohistochemistry of primary PDAC tumors and liver metastases, we confirmed high mesothelin (MSLN) expression on tumor cells, and CD70 expression on tumor cells and predominantly CAFs. Based on these results and the favorable safety profile of CAR natural killer (NK) cells over CAR T cells, we generated MSLN- and CD70-targeting IL-15-armored CAR NK cells. Both constructs mediated cytotoxicity against different pancreatic cancer and CAF cell lines with varying antigen expression in vitro, demonstrating that both, the CAR-molecule and IL-15 were required to increase functionality against more treatment-resistant cell lines. Interestingly, pooled MSLN- and CD70-CAR NK cells did not significantly improve cytolysis compared to monotherapies in an advanced 3D in vitro model or in vivo. Together these findings highlight the limitations of dual-targeting approaches and underscore the need for advanced engineering strategies to improve CAR NK cells beyond antigen targeting and cytokine support in the PDAC microenvironment.
    Keywords:  CAR NK cells; CD70; IL-15; mesothelin; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.omton.2026.201316
  6. EMBO Mol Med. 2026 Aug 27.
    A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.
    Tingxi Guo, Kaya R Epstein, Maegan E Hoover, Nathan W Zammit, Jennifer Y Yam, Scott Hussell, Sophia Hernandez, Abigail Doherty, Payam Zarin, Martina Sassone-Corsi, Lindsay Webb, Gene I Uenishi, Thomas Wickham, Christopher L Moore.
      Allogeneic cell therapies offer a scalable and off-the-shelf alternative to the autologous approach, but immune rejection, particularly by natural killer (NK) cells following human leukocyte antigen (HLA) ablation, remains a major barrier to their persistence. Here, we report an improved synthetic NKG2A engager to selectively inhibit NKG2A⁺ NK cells while avoiding activation of NKG2C⁺ subsets, thereby overcoming a key limitation of the natural ligand HLA-E. Engineered regulatory T cells (EngTregs) lacking HLA and expressing the engager were protected from in vitro NK cell-mediated cytotoxicity more effectively than previously reported NK inhibitory strategies. In humanized mouse models, EngTregs persisted for up to 12 weeks, whereas unprotected cells were rapidly rejected. Incorporation of the engager into a clinically compatible dual-AAV EngTregs preserved Treg identity and function while conferring resistance to immune rejection. Together, these findings establish the improved NKG2A engager as an effective synthetic immune-evasion strategy and provide a clinically translatable approach to enable durable persistence of off-the-shelf EngTreg therapies.
    DOI:  https://doi.org/10.1038/s44321-026-00507-4
  7. PLoS Pathog. 2026 Aug;22(8): e1014539
    The long and winding road: On the endoplasmic reticulum of Plasmodium and implications for pathogenesis.
    Antonia Blank, Solomon Ngwira, Manuel A Fierro.
      As a eukaryote, Plasmodium, the causative agent of malaria, is reliant on its endoplasmic reticulum (ER) for survival. However, as a protozoan pathogen, Plasmodium has also adapted its ER to support its parasitic lifestyle. This Pearl focuses on the interplay between conserved ER functions in Plasmodium such as cell signaling, protein synthesis/secretion, lipid production, and cellular stress, and their contribution to parasite pathogenesis. We further summarize the current knowledge about the role of the ER in pathogenic processes such as motility, egress/invasion, host-cell remodeling, and transmission throughout the blood, liver, sexual, and mosquito stages. Collectively, we hope that discussing the Plasmodium ER as both a conserved cellular hub and a source of parasite-specific biology offers promising opportunities for antimalarial strategies.
    DOI:  https://doi.org/10.1371/journal.ppat.1014539
  8. Gels. 2026 Aug 01. pii: 678. [Epub ahead of print]12(8):
    Cell-Type-Tailored Hydrogels for Adoptive Cell Therapy in Cancer.
    Jin Hak Shin, Yeonju Song, Jeehun Park.
      Hydrogel-enabled adoptive cell therapy (ACT) offers a localized and controllable strategy for improving cellular immunotherapy in solid tumors. Hydrogels can enhance cell retention and persistence, support immune cell function within the tumor microenvironment, and reduce systemic toxicity associated with broadly delivered immune stimulants. However, delivery of living immune cells imposes practical constraints on hydrogel selection, including cytocompatible encapsulation, minimal handling and injection stress, adequate transport of oxygen and soluble cues, and an appropriate balance between local retention and timely cell egress. This review summarizes natural, synthetic, and hybrid hydrogel platforms and compares physical/supramolecular assembly, covalent and enzymatic crosslinking, and photo-crosslinking. Injectable in situ-forming depots and shear-thinning/self-healing gels are highlighted for locoregional administration. Key design and reporting dimensions of hydrogels are linked to immune cell outcomes relevant to ACT. These properties include mechanics and viscoelasticity, porosity and mass transport, degradability and remodeling, bioadhesion and extracellular matrix (ECM) mimicry, and immunogenicity versus immune shielding. Finally, a cell-type-tailored framework is presented for chimeric antigen receptor T (CAR-T), T cell receptor-engineered T (TCR-T), and tumor-infiltrating lymphocyte (TIL) products, natural killer (NK) cells, and dendritic cells (DCs) or macrophage/monocyte-derived effectors. Distinct biological requirements are used to motivate corresponding material architectures and cue presentation strategies. The review also provides quantitative reporting guidance, identifies evidence gaps for γδ T cells, and discusses in vivo validation, combination ACT strategies, and translational handling constraints.
    Keywords:  CAR-NK cells; CAR-T; adoptive cell therapy; cancer immunotherapy; dendritic cells; gamma-delta T cells; granular hydrogels; immune cell delivery; injectable hydrogels; macrophage engineering
    DOI:  https://doi.org/10.3390/gels12080678
  9. Cell Rep Med. 2026 Aug 28. pii: S2666-3791(26)00429-5. [Epub ahead of print] 103012
    Inhibition of the lipocalin-2-phosphatidylserine axis restores natural killer cell immune surveillance.
    Jingkun Qin, Xinyu Hu, Lei Wang, Ying Cai, Ziming Hu, Xiuxiu Xu, Zhigang Nian, Zhenbang Liu, Xiaoyu Ding, Yan Jiang, Yuanhao Lin, Ke Ruan, Binqing Fu, Zhigang Tian, Yonggang Zhou, Haiming Wei.
      Lipid metabolic reprogramming can facilitate immune escape by promoting a suppressive phenotype in tumor-infiltrating immune cells, although this process remains poorly understood. Here, we identify the lipoprotein, Lipocalin-2 (LCN2), as an essential factor driving natural killer (NK) cell dysfunction and immunosuppressive phenotype. Spatial metabolomics with crystal structure analysis demonstrates that LCN2 binding to phosphatidylserine (PS) and PS enrichment is required for tumor-associated lipid reprogramming. Increased LCN2-PS binding limits IL-15-mediated JAK-STAT pathway activation in NK cells, while inhibiting tumor-infiltrating neutrophil maintenance of anti-tumor potential in NK cells via suppression of IFN-I response. Structure-based drug screening identifies semapimod as an LCN2 inhibitor that blocks interaction with PS, disrupting the LCN2-PS immunosuppressive axis and inducing tumor control. Overall, this study uncovers a lipid metabolic reprogramming mechanism that mediates innate immune evasion and proposes a tumor treatment strategy through enhanced innate immune surveillance.
    Keywords:  NK cell exhaustion; immune evasion; immunotherapy; lipid metabolism; lipocalin-2; phosphatidylserine; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103012
  10. Methods Mol Biol. 2026 Aug 25.
    Automated Deep Learning Protocol for Quantifying Cell Viability in Live/Dead Fluorescence Microscopy.
    Álvaro Díaz Vera, Khan Sharun, Shajahan Amitha Banu, Cristian Pablo Pennisi.
      The assessment of live/dead cells by means of fluorescence microscopy is a standard technique for assessing cell viability but relies on manual counting, which is laborious and prone to operator bias. Here we present a step-by-step protocol for automated cell viability quantification from two-channel live/dead fluorescence images using a deep learning pipeline built on a U-Net architecture with a ResNet-50 encoder pretrained on ImageNet. The protocol is organized into two tracks: a no-code inference track that applies a pre-trained model to standard live/dead images and an adaptation track for generating custom annotations and retraining the model for new cell types or staining protocols. The pipeline integrates percentile-based normalization, centroid-based (weakly supervised) annotation, patch-based transfer learning, and distance-transform watershed post-processing for instance-level counting. On an independent 25-image test set of human dermal fibroblasts, the model achieved counting R2 values of 0.986 (live) and 0.999 (dead) and a mean absolute viability error of 0.61 percentage points, providing a reproducible framework adaptable to diverse cell types and imaging platforms.
    Keywords:  Bioimage analysis; Cell counting; Cell viability; Deep learning; Fluorescence microscopy; Instance segmentation; Live/dead assay; Semantic segmentation; Transfer learning; Weakly supervised learning
    DOI:  https://doi.org/10.1007/7651_2026_715
  11. Biomaterials. 2026 Aug 19. pii: S0142-9612(26)00592-2. [Epub ahead of print]337 124568
    A biphasic hydrogel prevents glioblastoma recurrence by activating an EZH2-NeuroD1-SRCIN1 neuronal conversion axis.
    Yinqiu Tan, Qi Tang, Ting Lai, Yuntao Li, Chaolu Han, Baichen Liu, Libo Sun, Runkang Wang, Feng Lyu, Feng Wan, Qi Liu, Hongbo Zhang, Fulvio Reggiori, Xiaobing Jiang, Cuifeng Wang.
      Glioblastoma (GBM) recurrence upon resection remains a pivotal challenge in brain cancer treatments. The proneural transcription factor NeuroD1 holds potential to reprogram residual GBM cells into neurons to prevent recurrence. However, it can also act as a tumor initiation and maintenance factor in GBM. Here, we define an EZH2-NeuroD1-SRCIN1 therapeutic axis. Within this axis, inhibition of the lysine methyltransferase EZH2 decreases histone H3 lysine 27 trimethylation (H3K27me3) that leads to chromatin opening, which in turn enhances the expression and activity of endogenous and exogenously delivered NeuroD1. This initiates a GBM-to-neuron conversion while suppressing GBM cell proliferation in vitro through the induction of the neurogenesis-associated protein SRCIN1. To maintain the long-term neuronal reprogramming efficiency, we developed a biphasic hydrogel (biHG) for the co-delivery of an EZH2 inhibitor and exogenous NeuroD1 into the resection cavity in both murine syngeneic and human xenograft orthotopic GBM resection models. This strategy not only significantly impedes tumor recurrence but also successfully reprograms residual GBM cells into neuron-like cells with partial functionality, exhibiting a predominantly VGLUT1-positive glutamatergic phenotype. Thus, targeting EZH2 to sensitize GBM cells for NeuroD1-SRCIN1-mediated neuronal conversion represents a promising therapeutic approach against post-surgical GBM recurrence.
    Keywords:  Biphasic hydrogel; EZH2 inhibition; Glioblastoma; NeuroD1; Neuronal conversion; SRCIN1
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124568
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