bims-nakice Biomed News
on Natural killer cells
Issue of 2026–09–20
fourteen papers selected by
Santosh Phuyal, Oslo Universitetssykehus
  1. Synergistic restoration of NK cell cytotoxicity against solid tumors via sLTA-mediated dual-action modulation.
  2. PBMC-derive eNK cells was armed and promoted CAR-like response against tumors through armed with 16Fc21, a novel bispecific fusion protein for NK cells.
  3. Spatially instructed checkpoints in antitumor NK cell immunity.
  4. A Multimodal Framework to Guide Solid Tumor Indications for Natural Killer Cell-Based Therapy.
  5. IL-15 signaling during a critical NK cell developmental window subverts maturation and KIR acquisition.
  6. Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability.
  7. Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
  8. Tumour cells shape their environment to protect them from the immune system.
  9. Localized disruption of the presynaptic endoplasmic reticulum in Atlastin mutants.
  10. Protocol for robust gene knockout and reliable validation in human cell lines using quad-guide RNA vectors.
  11. Donor NKG2A/NKG2C Immunophenotype Influences the GMP-Compliant Manufacturing Potential of NK Cells for Adoptive Immunotherapy.
  12. Protocol for designing and evaluating antibody-drug conjugates to promote endocytosis and lysosomal trafficking.
  13. Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
  14. 'Stomach bugs' send protective immune cells rushing from gut to brain.
  1. Mol Biol Rep. 2026 Sep 16. pii: 1583. [Epub ahead of print]53(1):
    Synergistic restoration of NK cell cytotoxicity against solid tumors via sLTA-mediated dual-action modulation.
    Dobin Choi, Hyeoungeun Kim, Hangeun Kim, Dae-Kyun Chung.
       BACKGROUND: Natural killer (NK) cell-based immunotherapy has shown limited efficacy against solid tumors due to impaired NK cell activation and intrinsic tumor resistance. This study investigated whether lipoteichoic acid isolated from Latilactobacillus sakei K101 (sLTA) could overcome NK resistance in HT-29 colon cancer cells.
    METHODS AND RESULTS: Using an NK3.3/HT-29 co-culture system, we found that IL-2-activated NK cells alone were insufficient to induce robust cytotoxicity, whereas sLTA restored NK-mediated tumor cell killing. sLTA upregulated NK activating receptors, including NKG2D and natural cytotoxicity receptors, while enhancing MICB expression and suppressing Bcl-2 and other anti-apoptotic genes in HT-29 cells. siRNA-mediated knockdown and Western blot analysis confirmed the involvement of Caspase-3-dependent apoptosis. Transwell and neutralization assays further demonstrated that sLTA-primed HT-29 cells were sensitized to contact-independent cytotoxicity mediated by NK-derived TNF-α and IFN-γ.
    CONCLUSIONS: sLTA functions as a dual-action immune sensitizer by enhancing NK effector activation and lowering the apoptotic threshold of resistant tumor cells. These findings suggest that sLTA may serve as an adjunct strategy to improve NK cell-based immunotherapy against solid tumors.
    Keywords:   Latilactobacillus sakei ; Colon cancer cells; Lipoteichoic acid; Natural killer cells; Probiotics; Tumor resistance to NK cells
    DOI:  https://doi.org/10.1007/s11033-026-12764-0
  2. Front Immunol. 2026 ;17 1875554
    PBMC-derive eNK cells was armed and promoted CAR-like response against tumors through armed with 16Fc21, a novel bispecific fusion protein for NK cells.
    Yangyang Li, Yehai Wang, Ximeng Zhang, Yan Fan, Lina Pan, Jing Wu, Weihua Xiao.
       Introduction: Cell-based immunotherapies of PBMC-derive Natural killer (NK) cells have demonstrated substantial potential for the treatment of hematologic malignancies. However, its application is limited due to the complex and inefficient gene modification in vitro and the insufficient therapeutic efficacy against solid tumors in vivo.
    Methods: Herein, a novel bispecific fusion protein 16Fc21(Anti-CD16A-FC-IL21) with capacity of modulate NK cell function is designed and constructed to try to breakthrough these limitations.
    Results: In this work, we demonstrated that 16Fc21 has excellent ability to induce the functional activation of PBMC-derived NK cells and improve the therapeutic efficacy of NK cell immunotherapy for solid tumors in vivo. Additionally, we developed a novel combination therapy by combining adoptive transfer of NK cell with 16Fc21. We pre-arming 16Fc21 onto the surface of NK cells and successfully developed a non-genetically modified 16Fc21 armedNK (16Fc21 armed-eNK) technology platform.
    Discussion: We confirmed that this novel combination therapy can effectively improve the survival and proliferation of NK cells in vivo, offering a safer and more effective way to enhance their therapeutic effects in vivo. This approach provides a solution to the challenges of the cumbersome in vitro gene modification of PBMC-derived NK cells and their insufficient therapeutic in vivo.
    Keywords:  CAR-NK; NK cell immunotherapy; Pichia (Komagataella) pastoris; armed-NK; bispecific fusion protein; natural killer (NK) cell
    DOI:  https://doi.org/10.3389/fimmu.2026.1875554
  3. Trends Immunol. 2026 Sep 14. pii: S1471-4906(26)00228-0. [Epub ahead of print]
    Spatially instructed checkpoints in antitumor NK cell immunity.
    Ruifeng Wang, Peng Sun, Cheng Sun.
      Natural killer (NK) cell immunotherapies remain less effective in solid tumors than in hematologic malignancies. Poor infiltration, checkpoint engagement, and metabolic stress contribute, but these mechanisms often operate within spatially organized niches. We develop the concept of spatially instructed checkpoints: inhibitory programs locally induced or maintained whose functional impact depends on position. We organize evidence across tissue-level exclusion, suppressive cellular neighborhoods, and the cytotoxic synapse, distinguishing causal findings from associations and hypotheses. Spatial organization is an integrating layer that interacts with, rather than replaces, intrinsic, soluble, metabolic, transcriptional, and epigenetic mechanisms. We propose a translational framework for converting spatial discoveries into deployable assays that identify the dominant barrier and guide mechanism-matched strategies to restore antitumor NK cell activity.
    Keywords:  NK cells; cancer immunotherapy; immune checkpoints; solid tumors; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2026.08.012
  4. Eur J Immunol. 2026 Sep;56(9): e70283
    A Multimodal Framework to Guide Solid Tumor Indications for Natural Killer Cell-Based Therapy.
    L Chiossone, V Picant, Q Barbier, T A Fehniger, Eric Vivier.
      T cell-based immunotherapies have achieved remarkable success in hematological malignancies but remain limited in solid tumors. Natural killer (NK) cells offer a compelling complementary approach, given their ability to recognize and kill tumor cells independently of neoantigen presentation and MHC class I expression. This study integrates multiomic analyses, clinical trial data, and transcriptomic analyses to systematically identify solid tumor indications most likely to benefit from NK cell-based therapies. Immunohistochemical analysis revealed that NK cells infiltrate multiple tumor types, with the highest abundance in kidney tumors. Systematic review of 177 clinical trials identified variable efficacy across solid tumor indications, without a clearly superior tumor type or intervention. Transcriptomic profiling of over 10,000 TCGA samples assessed NK cell infiltration, cytotoxic fitness, and tumor microenvironment composition, highlighting kidney renal cell carcinoma, lung adenocarcinoma and squamous cell carcinoma, cervical and endocervical cancers, and mesothelioma as promising candidates for future clinical evaluation. Together, these findings provide a multimodal framework to prioritize tumor indications and improve the rational design of future NK cell clinical trials.
    Keywords:  cancer research; clinical trial; immunotherapy; medicine; natural killer cell; transcriptome; tumor microenvironment
    DOI:  https://doi.org/10.1002/eji.70283
  5. Cell Rep. 2026 Sep 16. pii: S2211-1247(26)01077-6. [Epub ahead of print]45(10): 117999
    IL-15 signaling during a critical NK cell developmental window subverts maturation and KIR acquisition.
    Michael A Ruesch, Noah T Koenigs, Ella Troy, Caprice D Eisele, Megan J Broughton, Isaac Elmer, Kyoko Yamaguchi, Kinda Sara, Ansel P Nalin, Amir Horowitz, Roshini S Abraham, Stephen K Anderson, Bethany L Mundy-Bosse, Christopher C Oakes, Aharon G Freud.
      Natural killer (NK) cells are key mediators of immune surveillance following hematopoietic stem cell transplantation (HSCT). However, despite the post-conditioning spike in interleukin-15 (IL-15), NK cell maturation is frequently delayed following HSCT. Here, we show that during in vitro NK cell development from CD34+ hematopoietic progenitor cells, early exposure to IL-15 drives aberrant mTOR activation, resulting in DNA methylation and transcriptional dysregulation with suppressed maturation and KIR acquisition. In contrast, transiently withholding IL-15 or inhibition of mTOR with rapamycin generates NK cell developmental intermediates intrinsically poised to mature into highly functional, KIR-expressing NK cells. Single-cell analysis of HSCT patients at early post-transplant time points reveals a similar aberrant transcriptional signature of IL-15/mTOR overactivation in circulating donor-derived NK cells. These findings identify a developmental window when IL-15 signaling can paradoxically subvert NK cell maturation and KIR acquisition, suggesting that temporally regulated cytokine signaling could accelerate immune reconstitution and improve therapeutic efficacy.
    Keywords:  CP: immunology; HSCT; IL-15; KIR; NK; NK cell development; hematopoietic stem cell transplant; interleukin-15; killer immunoglobulin-like receptor; mTOR; natural killer cell
    DOI:  https://doi.org/10.1016/j.celrep.2026.117999
  6. Elife. 2026 Sep 14. pii: RP104951. [Epub ahead of print]14
    Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability.
    Darren Wethington, Saeed Ahmad, Marc Potempa, Giuseppe Giuliani, Oscar A Aguilar, Maheshwor Poudel, Simon Grassmann, William C Stewart, Nicholas M Adams, Joseph C Sun, Lewis L Lanier, Jayajit Das.
      Natural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection in C57BL/6 mice can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. For example, clones derived from single cells are most abundant during expansion when they are primarily CD27- for NK cells and CD62L- for T cells, phenotypes derived from precursor CD27+ and CD62L + cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27- NK cells and a highly proliferative CD27-Ly6C- mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cell subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.
    Keywords:  MCMV infection; Master equation; NK cell clonal expansion; clonal heterogeneity; computational biology; immunology; inflammation; memory NK cells; mouse; stochastic fluctuations; systems biology
    DOI:  https://doi.org/10.7554/eLife.104951
  7. Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):
    Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
    Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.
      Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-76619-9
  8. Nature. 2026 Sep 16.
    Tumour cells shape their environment to protect them from the immune system.
      
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-02703-1
  9. J Cell Sci. 2026 Sep 14. pii: jcs.265223. [Epub ahead of print]
    Localized disruption of the presynaptic endoplasmic reticulum in Atlastin mutants.
    Mónica C Quiñones-Frías, Dina M Ocken, Avital A Rodal.
      The endoplasmic reticulum (ER) extends throughout neurons and regulates many functions, including neurite outgrowth, neurotransmission, and synaptic plasticity. Mutations in ER-shaping proteins cause the neurodegenerative disorder Hereditary Spastic Paraplegia (HSP), yet the ultrastructure and dynamics of neuronal ER remain largely unexplored, especially at presynaptic terminals. Using super-resolution and live imaging in Drosophila larval motor neurons, we investigated ER structure in wild-type animals and mutants of the HSP-linked gene, Atlastin, which encodes an ER-shaping protein. Previous studies reported diffuse localization of an ER luminal marker at Atlastin mutant presynaptic terminals, which was attributed to ER fragmentation. Using an ER membrane marker, we found that Atlastin mutant ER forms robust networks with only mild defects in structure and dynamics, indicating that the primary defect is functional rather than architectural. We demonstrate that Atlastin mutants progressively displace a luminal ER protein reporter to the cytosol during larval development, specifically at synapses, while this reporter remains correctly localized in cell bodies, axons, and muscles. This synapse-specific displacement phenotype, previously unreported in non-neuronal cells, emphasizes the importance of studying neurons to understand HSP pathogenesis.
    Keywords:   Drosophila ; Atlastin; Endoplasmic Reticulum; Synapse
    DOI:  https://doi.org/10.1242/jcs.265223
  10. STAR Protoc. 2026 Sep 16. pii: S2666-1667(26)00490-9. [Epub ahead of print]7(4): 104837
    Protocol for robust gene knockout and reliable validation in human cell lines using quad-guide RNA vectors.
    Michael Tobin, Jie Dai, Li-Chuan Chan, Weiwei Guo.
      CRISPR-Cas9 is a powerful tool for editing genomic loci, however achieving high knockout efficiency at certain targets remains challenging. Here, we present a protocol for gene knockout using an all-in-one, quad-guide RNA-expressing vector. We describe steps for plasmid construction, virus preparation, transduction, and subsequent gene editing and functional validation within DLD-1 colorectal adenocarcinoma cells. This strategy provides an efficient workflow for gene knockout that is rapidly confirmed through PCR amplification of mRNA derived from the targeted gene loci.
    Keywords:  Biotechnology and bioengineering; CRISPR; Genetics
    DOI:  https://doi.org/10.1016/j.xpro.2026.104837
  11. Cancers (Basel). 2026 Aug 23. pii: 2732. [Epub ahead of print]18(17):
    Donor NKG2A/NKG2C Immunophenotype Influences the GMP-Compliant Manufacturing Potential of NK Cells for Adoptive Immunotherapy.
    Rut Meseguer, Cristobal Aguilar, Paula Amat, Luis Larrea, Ana Bonora, Pedro Chorão, Francisco Boix, Jose Luis Piñana, Rosa Guerrero, Pau Montesinos, Belén Vera, Dolores Planelles, Mar Luis, Jose Luis Poveda, Javier De la Rubia, Sergi Querol, Cristina Arbona, Manuel Guerreiro, Carlos Solano.
      Background: Relapse and opportunistic viral infections remain major causes of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adoptive transfer of natural killer (NK) cells is a promising strategy to enhance post-transplant immune reconstitution. Adaptive NKG2C+ NK cells exhibit enhanced cytotoxicity and persistence, but the influence of baseline donor immunophenotype on GMP manufacturing has not been systematically investigated. We evaluated whether donor NKG2A/NKG2C immunophenotypes are associated with successful manufacture of adaptive NK-cell products. Methods: Eighty-three healthy donors from the ReDoCel registry underwent immunophenotypic characterization of circulating NK-cell subsets by multiparametric flow cytometry. Donors were stratified by unsupervised hierarchical clustering according to NKG2A/NKG2C expression. Representative donors from NKG2C- and NKG2A-dominant clusters underwent feeder-free GMP-compliant expansion using the automated CliniMACS Prodigy® platform (Miltenyi Biotec, Bergisch Gladbach, Germany). Expanded products were evaluated for manufacturing efficiency, immunophenotype, cytotoxic function, and post-thaw stability. Results: Baseline NKG2C frequencies showed marked inter-donor variability, allowing identification of four immunophenotypic clusters. Only the NKG2C-dominant donor achieved successful GMP manufacturing, exceeding the predefined expansion threshold while maintaining high viability and purity. Both NKG2A-dominant donors showed limited proliferative capacity under identical manufacturing conditions. Expanded NK cells acquired an activated phenotype characterized by increased expression of DNAM-1, NKG2D, NKp30, NKp46, and TIM-3 while preserving mature differentiation and KIR expression. Functional analyses demonstrated potent degranulation against leukemia targets with minimal autoreactivity, resulting in a predominantly cytotoxic effector profile. The successfully expanded product maintained viability, phenotype, and function after long-term cryopreservation. Conclusions: This proof-of-concept study suggests that baseline donor NKG2A/NKG2C immunophenotype may influence GMP manufacturing of adaptive NK-cell products. These findings support prospective evaluation of donor immunophenotyping as a biomarker for donor qualification and manufacturing optimization to facilitate standardized off-the-shelf adaptive NK-cell therapies after allo-HSCT.
    Keywords:  GMP manufacturing; NKG2A; NKG2C; adaptive NK cells; adoptive immunotherapy; allogeneic hematopoietic stem cell transplantation; cytomegalovirus; natural killer cells
    DOI:  https://doi.org/10.3390/cancers18172732
  12. STAR Protoc. 2026 Sep 17. pii: S2666-1667(26)00499-5. [Epub ahead of print]7(4): 104846
    Protocol for designing and evaluating antibody-drug conjugates to promote endocytosis and lysosomal trafficking.
    Xinlei Zhuang, Li Lin, Liqiang Pan.
      Receptor endocytosis and lysosomal delivery are critical for efficient intracellular delivery of antibody-drug conjugates (ADCs), yet many cancer targets exhibit limited internalization. Here, we present a protocol for engineering and evaluating ADCs to induce receptor ubiquitination, thereby promoting receptor uptake and transport toward lysosomal compartments. We describe steps for designing antibodies fused with E3 ligase-binding modules, drug conjugation, and cellular assays to quantify ubiquitination-dependent internalization and lysosomal accumulation in cancer cell models. For complete details on the use and execution of this protocol, please refer to Zhuang et al.1.
    Keywords:  Biotechnology and bioengineering; Flow Cytometry; Microscopy; Protein expression and purification; SPR; Surface plasmon resonance; antibody
    DOI:  https://doi.org/10.1016/j.xpro.2026.104846
  13. Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):
    Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
    Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.
      Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-77423-1
  14. Nature. 2026 Sep 15.
    'Stomach bugs' send protective immune cells rushing from gut to brain.
    Gemma Conroy.
      
    Keywords:  Brain; Immunology; Infection
    DOI:  https://doi.org/10.1038/d41586-026-02891-w
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