bims-nakice Biomed News
on Natural killer cells
Issue of 2026–06–07
thirteen papers selected by
Santosh Phuyal, Oslo Universitetssykehus
  1. Autophagy supports the storage of lytic granules in human NK cells.
  2. HIV tri-specific killer engagers directly enhance NK cell function and safely expand NK cells in vivo.
  3. CD36 aggravates ferroptosis in NK cells and dampens their anti-fibrotic activity in the liver.
  4. A Unique Intraexonic Splicing Mechanism in the Immunoglobulin Domain of NKp30 Produces a Surface-Expressed Receptor With Altered Ligand Specificity.
  5. Natural killer cells swarm and cross-recruit cytotoxic T cells via CCR5.
  6. Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer.
  7. Circumventing IFN-γ induced resistance in ovarian cancer with a double-hit: NKG2A knockout of PRAME-TCR expressing NK cells.
  8. Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy.
  9. Comparative proteome analyses of human natural killer cells from patients after allogeneic stem cell transplantation and healthy individuals challenged with Aspergillus fumigatus.
  10. Uveal melanoma: A review of current treatment limitations and the emerging therapeutic potential of natural killer cells.
  11. Ionic regulation of cancer cell stiffness and metastatic colonization via the MRTFA-KCNMB1 axis.
  12. Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense.
  13. Bang! Exploding immune cells splatter potent toxins everywhere.
  1. Cell Death Dis. 2026 Jun 01.
    Autophagy supports the storage of lytic granules in human NK cells.
    Piera Filomena Fiore, Sergio Forcelloni, Simone Vitozzi, Nicola Tumino, Tobias Theinert, Lokossou William Sanvi, Francesca Nazio, Valentina D'Oria, Stefania Martini, Maximilian Reichert, Lorenzo Moretta, Ignazio Caruana, Paola Vacca.
      Natural Killer (NK) cells are innate lymphoid cells that play an important role in immune defense against pathogens and tumors. Understanding the mechanisms that enhance NK cell effector functions could significantly improve current NK cell-based therapies. Autophagy is a lysosome-dependent degradation process essential for NK cell development and function. This study analyzed the autophagic potential of mature NK cell subsets in peripheral blood. We demonstrated that exposure to inflammatory cytokines reduces autophagy via mTOR signaling pathway. Specifically, the activation of NK cell receptors leads to a temporary decrease in autophagy, which is rapidly restored, demonstrating the dynamics of autophagy in response to activating signals. Importantly, continuous overexpression of key autophagy regulators significantly increased autophagic flux, which directly correlated with enhanced cytotoxicity and metabolic activity in NK cells. The increased cytotoxicity was supported by a greater accumulation of cytolytic granules and their associated proteins. Our findings indicate that activating stimuli reduce autophagy, whereas sustained autophagic activity under steady-state conditions is crucial for the formation and maintenance of cytolytic granules, supporting the persistent cytotoxic function of NK cells.
    DOI:  https://doi.org/10.1038/s41419-026-08937-1
  2. Cell Rep Med. 2026 Jun 04. pii: S2666-3791(26)00264-8. [Epub ahead of print] 102847
    HIV tri-specific killer engagers directly enhance NK cell function and safely expand NK cells in vivo.
    Ross T Cromarty, Julien A Clain, Yvette Soigner, Tumpa Dasgupta, Kate Dixon, Kevin Nguyen, Hannah Flores, Emma Eungard, Joshua Walker, Josh Bjorgen, Martin Felices, Justin Harper, Timothy W Schacker, Zachary Davis, Mirko Paiardini, Jeffrey S Miller.
      An HIV cure remains elusive, and many individuals develop comorbidities; therefore, new synergistic strategies to combat HIV are needed. Enhanced natural killer (NK) cell function associates with HIV elite control, primarily through antibody-dependent cellular cytotoxicity (ADCC). We generated tri-specific killer engagers (TriKEs) to enhance NK cell responses against HIV-infected cells. HIV TriKEs, one using the VRC01/07 antibody domains (VRC TriKE) and one using the CD4 ectodomain 1 (CD4 TriKE), promote NK cell function and killing of HIV target cells. NK cells expressing both CD38 and CD57 are major mediators of this function. We performed a dose-escalation study in SIV-uninfected rhesus macaques to assess the safety and pharmacodynamics of our CD4 TriKE. The TriKE is safe and effective at expanding peripheral and lymphoid NK cells in vivo. These findings support TriKEs as a promising safe immunotherapy to recognize and kill HIV-infected cells, with potential for combination cure strategies.
    Keywords:  ADCC; HIV; NK cells; immunotherapy; tri-specific killer engagers
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102847
  3. Front Immunol. 2026 ;17 1825015
    CD36 aggravates ferroptosis in NK cells and dampens their anti-fibrotic activity in the liver.
    Xiaokun Shen, Haitao Cao, Fujie Li, Wenya Wang, Xingshu Qi, Yarui Zhou, Bo Li, Qingjie Fan, Tao Yang, Shinan Li.
      Liver fibrosis is a major global health challenge, and it is an independent risk factor for the development of hepatocellular carcinoma (HCC). Several methods have been explored to improve liver fibrosis progression, but effective preventive and therapeutic strategies remain limited. Natural killer (NK) cells can limit the activation of hepatic stellate cells (HSCs), but they have exhibited impaired antifibrotic properties in liver fibrosis, and the underlying mechanisms are not well understood. In this study, we found that CD36 was markedly upregulated in NK cells from mice with liver fibrosis. The CD36 expression was negatively correlated with activation markers of NK cells. The CD36- NK cells exhibited elevated cytotoxic cytokine production and enhanced antifibrotic activity against HSCs. The adoptive transfer of CD36- NK cells alleviated liver fibrosis progression. Mechanistically, CD36 induced reactive oxygen species (ROS) and lipid peroxidation. These consequently triggered ferroptosis in NK cells. The blockage of CD36 or inhibition of ferroptosis in NK cells effectively restored their antifibrotic properties against HSCs. In summary, our findings demonstrated that the antifibrotic properties of NK cells were regulated by CD36. These results provide evidence that targeting CD36 could restore NK cell function for liver fibrosis immunotherapy.
    Keywords:  CD36; NK; cell therapy; ferroptosis; liver fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1825015
  4. Eur J Immunol. 2026 Jun;56(6): e70215
    A Unique Intraexonic Splicing Mechanism in the Immunoglobulin Domain of NKp30 Produces a Surface-Expressed Receptor With Altered Ligand Specificity.
    Elisabeth G Bjørnsen, Ellen Sofie Pete, Hanna Chan, Marit Inngjerdingen, Tatyana Sandalova, Anne Spurkland, Michael R Daws, Adnane Achour, Andreas Lossius, Erik Dissen.
      The activating receptor NKp30 is important in NK cell killing of cancer cells. Here, we demonstrated that a pair of splice signals in the Ig domain exon of human NKp30 is largely conserved among primates and placental mammals and produces an alternatively spliced NKp30 ectodomain (NKp30-S) with an in-frame, nonartefactual deletion of 25 amino acid residues. Transfection yielded NKp30-S bands in NKL cells but not in 293T cells, suggesting that the splicing mechanism is cell-specific. Molecular modeling indicated that the overall folding of NKp30-S is maintained compared with NKp30. NKp30-S was expressed at the cell surface but did not bind to the NKp30 ligand B7H6 in soluble fusion protein or reporter cell assays. Single-cell RNA sequencing showed that NKp30-S transcription was not restricted to major NK cell subsets but suggested that a small fraction of blood NK cells expressed only the NKp30-S splice variant. The ratio of NKp30-S to full-length transcript was increased after activation of blood NK cells with IL-2 or IL-15 or crosslinking with anti-CD16 antibody, suggesting that this unique splicing mechanism, not seen in other Ig superfamily proteins, is regulated and may play a role in modulating NK cell responsiveness toward B7H6+ cancer cells in vivo.
    Keywords:  NK cell; mRNA splicing; protein structure; receptors
    DOI:  https://doi.org/10.1002/eji.70215
  5. Cell Rep. 2026 May 29. pii: S2211-1247(26)00493-6. [Epub ahead of print]45(6): 117415
    Natural killer cells swarm and cross-recruit cytotoxic T cells via CCR5.
    James Cremasco, Szun S Tay, Guiyuan Yang, Anne Huber, Daryan Kempe, Richard Tang, Feyza Colakoglu, Peter L H Newman, Xufeng Lin, Leonard D Goldstein, Conor J Kearney, Maté Biro.
      Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are being trialed as mediators of cellular immunotherapies, but the mechanisms by which these cytotoxic lymphocytes are recruited into solid tumors are incompletely understood. Here, we employ a combination of solid tumor models and quantitative imaging to investigate the interplay between NK cells engaging targets and distal cytotoxic lymphocytes. We find that both murine and human NK cells swarm to tumor targets via secretion of diffusive chemokines that bind the CCR5 receptor. Moreover, we show that activated NK cells and CTLs can directly cross-recruit one another via CCR5. By employing multi-step adoptive transfer protocols in vivo, we demonstrate that tumor-reactive NK cells promote the tumor infiltration of subsequently transferred NK cells and CTLs. Together, these results demonstrate that NK cells can swarm via homotypic chemokine signaling and that NK cells and CTLs engage in direct heterotypic cross-recruitment to targets.
    Keywords:  CCR5; CP: cancer; CP: immunology; T cells; cellular immunotherapy; chemokines; lymphocyte migration; lymphocyte signaling; natural killer cells; solid cancer immunotherapy; swarming
    DOI:  https://doi.org/10.1016/j.celrep.2026.117415
  6. Sci Immunol. 2026 Jun 05. 11(120): eaeb6645
    Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer.
    Clara Serger, Lucas Rebuffet, Michael T Sandholzer, Wiebke Rackwitz, Irene Fusi, Petra Herzig, Annalea Brüggemann, Carina A Pawlow, Evgeny Chichelnitskiy, Daniel Hajnal, Nicole Oelgarth, Sarp Uzun, Christoph Schultheiß, Andreas Zingg, Sofia Tundo, Thuy T Luu, Aljaz Hojski, Didier Lardinois, Lavinia Neubert, Mascha Binder, Kirsten Mertz, Marcel P Trefny, Nicole Kirchhammer, Marina Natoli, Matthias S Matter, Heinz Läubli, Christine Falk, Karin Schaeuble, Eric Vivier, Andrea Romagnani, Alfred Zippelius.
      Natural killer (NK) cell-targeting immunotherapies are emerging, yet the differentiation and functional states of tumor-infiltrating NK cells remain poorly understood. Using matched single-nucleus RNA and ATAC sequencing of samples from patients with non-small cell lung cancer (NSCLC), we resolved the transcriptional and epigenetic landscape of intratumoral NK cells. We identified two tumor-associated NK (taNK) cell subsets marked by expression of ITGAE (CD103) and ITGA1 (CD49a) that display features of tissue residency and dysfunction while preserving cytotoxic function. Trajectory and regulon analyses revealed an inflammation-driven transition from early granzyme K (GZMK)+ NK cells toward an ENTPD1+ (CD39+) effector state characterized by interferon-stimulated gene (ISG) programs. Functional profiling established CD39+ taNK cells as the dominant cytotoxic NK cell population with superior killing capacity that was further potentiated by NKG2A blockade. This study offers mechanistic insights into NK cell differentiation in NSCLC and establishes CD39+ taNK cells as a targetable effector population for immunotherapy.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb6645
  7. J Ovarian Res. 2026 Jun 04.
    Circumventing IFN-γ induced resistance in ovarian cancer with a double-hit: NKG2A knockout of PRAME-TCR expressing NK cells.
    Els P van Hees, Oliva W Rensing, Renate S Hagedoorn, Cilia R Pothast, Anne K Wouters, Rosa A van Amerongen, J H Frederik Falkenburg, Rosa de Groot, Mirjam H M Heemskerk.
       BACKGROUND: The success of NK cell therapies against solid tumors remains limited, possibly due to tumor resistance mechanisms associated with the upregulation of inhibitory ligands. Previous studies have demonstrated that expanded NK cells can lyse ovarian cancer cells and produce IFN-γ. However, secretion of IFN-γ within the tumor microenvironment, leads to the upregulation of both classical HLA class I and the non-classical HLA-E on bystander tumor cells, thereby contributing to resistance against NK cell-mediated cytotoxicity. To overcome this IFN-γ induced resistance, we developed NKG2A-knockout NK: TCR cells targeting PRAME (NK: PRAMENKG2A KO), a tumor-associated antigen expressed in ovarian cancer.
    METHODS: Primary NK cells were isolated from PBMCs, stimulated with cytokines, and genetically modified using CRISPR-Cas9 to knockout the KLRC1 gene, which encodes NKG2A. After stimulation, the NK cells were further engineered to express the PRAME-specific TCR. NK: PRAMENKG2A KO were compared with control NK: PRAMENKG2A WT and NK: MOCKNKG2A KO cells for effector function against PRAME-positive ovarian cancer cell lines and primary ovarian cancer cells. To mimic the pro-inflammatory tumor environment, ovarian cancer cell lines were pre-treated with IFN-γ.
    RESULTS: First we observed that NK: PRAME cells without a KLRC1 knockout were not effective to lyse IFN-γ treated ovarian cancer cells, irrespective of upregulated HLA class I expression. To overcome HLA-E mediated inhibition, the CRISPR-Cas9 induced KLRC1 knockout was successfully achieved without negatively impacting NK: TCR cell engineering, expansion and further alterations in phenotype. As a result, the NK: PRAMENKG2A KO cells exhibited increased cytotoxicity against these IFN-γ treated tumor cells.
    CONCLUSIONS: This dual-targeting strategy offers a unique advantage by enabling the targeting of both HLA-positive and HLA-negative tumor cells, promoting a pro-inflammatory environment and enhancing the efficacy of TCR-based immunotherapy for ovarian cancer and other solid tumors.
    Keywords:  Cancer; Interferon-γ; NK cell therapy; Ovarian; TCR
    DOI:  https://doi.org/10.1186/s13048-026-02156-0
  8. J Immunother Cancer. 2026 Jun 03. pii: e014840. [Epub ahead of print]14(6):
    Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy.
    Anna Rita Redavid, Loredana Cifaldi, Roberto Bei, Emmanuel De Billy, Doriana Fruci.
      Natural killer (NK) cells are critical effectors of antitumor immunity, however their cytotoxic function is frequently impaired within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), the most abundant immune stromal population in solid tumors, play a central role in shaping NK cell responses through a broad range of mechanisms, including receptor-ligand interactions, immunosuppressive cytokine signaling, metabolic reprogramming, and engagement of immune checkpoint pathways. Here, we review current insights into the bidirectional crosstalk between TAMs and NK cells and discuss therapeutic strategies aimed at restoring NK cell activity by targeting TAMs. These include macrophage depletion and reprogramming approaches, modulation of metabolic and transcriptional pathways, and interventions targeting cytokine networks and immune checkpoints. We further examine emerging strategies that reshape the TME to enhance NK-macrophage cooperation, such as induction of inflammatory cell death, modulation of innate immune signaling pathways, and the development of synthetic NK cell engagers. In addition, we highlight the impact of macrophage ontogeny, tissue residency, and spatial organization on NK cell function, emphasizing how distinct microanatomical niches within the TME regulate immune cell interactions and influence therapeutic responses. Finally, we summarize translational advances and ongoing clinical efforts aimed at integrating TAM-targeted therapies with NK cell-based approaches. Collectively, these findings provide a conceptual and mechanistic framework for the rational design of combination immunotherapies that leverage macrophage-NK cell interactions to enhance innate immune responses and improve cancer treatment outcomes.
    Keywords:  Immunosuppression; Immunotherapy; Macrophage; NK Cell Lectin-Like Receptor Subfamily K; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2026-014840
  9. Microlife. 2026 ;7 uqag020
    Comparative proteome analyses of human natural killer cells from patients after allogeneic stem cell transplantation and healthy individuals challenged with Aspergillus fumigatus.
    Jan Springer, Matthias Drobny, Linda Heilig, Sabrina Kraus, Olaf Kniemeyer, Thomas Krüger, Christian Olischer, Lydia Bussemer, Gianni Panagiotou, Axel A Brakhage, Hermann Einsele, Sascha Schäuble, Jürgen Löffler.
      Natural killer (NK) cells contribute to the innate immune system and are pivotal for the defence against opportunistic pathogens, including fungi. Aspergillus fumigatus (AF), a filamentous mold, can cause invasive pulmonary aspergillosis in immunocompromised patients, e.g. in patients after allogeneic stem cell transplantation (alloSCT). In this pilot study, we challenged NK cell samples from alloSCT recipients collected 90, 120, and 180 days after transplantation and from healthy individuals with AF and characterize the proteome response differences. We identified 2259 differentially abundant proteins between the NK cell proteomes of alloSCT recipients and healthy individuals. Among these, 1118 proteins were differentially abundant at all time points and 1931 proteins specifically at day 180 post-alloSCT. Following stimulation of NK cells with AF, we found a profoundly different early proteome (day 90, n=1652 proteins), while at day 180, only 77 proteins remained significantly differentially abundant. We identified, among others, a major differentially abundant protein cluster related to IL27RA (including OAS, STAT1, and MX). Furthermore, for selected markers [granzyme A (GZMA), Neural Cell Adhesion Molecule 1 (NCAM1/CD56), perforin-1 (PRF1)], we confirmed our proteome data by flow cytometry in NK cells from an independent second patient and healthy individual cohort. In conclusion, we demonstrate the advantage of combining comprehensive proteomic profiling with targeted flow cytometry to investigate NK cell responses to AF. Our data analysis connects STAT1 with IL27RA as well as granzyme, IFNg, and NCAM1 activity, which may be exploited towards future therapeutics warranting confirmation in larger study cohorts.
    Keywords:  Aspergillus fumigatus, immune reconstitution; NK cells; Proteome analyses; allogeneic stem cell transplantation; fungal infection
    DOI:  https://doi.org/10.1093/femsml/uqag020
  10. J Invest Dermatol. 2026 May 30. pii: S0022-202X(26)01033-X. [Epub ahead of print]
    Uveal melanoma: A review of current treatment limitations and the emerging therapeutic potential of natural killer cells.
    Revu V L Narayana, Abbigail L Lanier, Narendra Wajapeyee, Romi Gupta.
      Uveal melanoma (UM) is the most common intraocular malignancy, contributing to ∼5% of all melanomas. It arises from melanocytes in the uveal tract (choroid, ciliary body, and iris) and has a specific genetic and clinical profile. Important genetic alterations shown to drive UM pathogenesis and influence prognosis include GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. In addition, monosomy 3 and 8q gains are strongly linked to poor outcomes, whereas disomy 3 and 6p gains are associated with better prognosis. Approximately half of patients with UM develop metastases, most commonly to the liver, leading to high mortality. Conventional chemotherapy has shown poor efficacy, and immune checkpoint inhibitors have demonstrated only modest benefits. The immunosuppressive tumor microenvironment, particularly in the liver, further limits treatment efficacy. NK cells offer a promising avenue to treat patients owing to their ability to recognize tumor cells independent of major histocompatibility complex. However, UM employs multiple immune evasion strategies, including the upregulation of HLA-E and the secretion of immunosuppressive factors inhibiting NK cell function. Despite these barriers, preclinical studies demonstrate that activated NK cells can reduce hepatic metastases. Emerging NK cell-based therapies, such as chimeric antigen receptor-engineered NK cells and NK cell engagers, could provide an effective therapeutic strategy to treat metastatic UM, warranting further clinical investigation.
    Keywords:  CAR-NK; Metastases; NK cells; TME; Uveal melanoma
    DOI:  https://doi.org/10.1016/j.jid.2026.03.036
  11. Dev Cell. 2026 Jun 02. pii: S1534-5807(26)00162-0. [Epub ahead of print]
    Ionic regulation of cancer cell stiffness and metastatic colonization via the MRTFA-KCNMB1 axis.
    Alexa M Gajda, Mohamed Haloul, Vinay Pai, Keyvan Mollaeian, Khushi J Patel, Raymundo Rodríguez-López, Katie M Beverley, Mark A Sanborn, Kihak Lee, Caitlyn C Castillo, Stephanie M Wilk, Beata M Wolska, Faruk Hossen, Eron N Mendenhall, James C Lee, Irena Levitan, Jalees Rehman, Ekrem Emrah Er.
      Cellular stiffness impacts multiple steps of cancer metastasis, but mechanisms that regulate the stiffness of cancer cells remain poorly understood. Here, we identified potassium efflux and potassium calcium-activated channel subfamily M regulatory beta subunit 1 (KCNMB1), an auxiliary subunit of the large conductance calcium-activated potassium (BK) channels, as regulators of cellular stiffness downstream of myocardin-related transcription factor A (MRTFA). In primary pericytes, KCNMB1 knockdown increased cellular stiffness, which is consistent with the role of potassium efflux in promoting relaxation during excitation-contraction coupling. In a striking contrast, however, KCNMB1 knockdown decreased cancer cells' stiffness. Softer cancer cells were resistant to natural killer (NK) cell mediated cytotoxicity and the low KCNMB1 expression was associated with reduced survival in breast cancer patients. Importantly, pharmacological activation of BK channels reduced metastatic burden in mice and improved lysis of cancer cells by cytotoxic T lymphocytes. These results highlight the ionic regulation of stiffness in cancer cells and point to BK channel agonism as a therapeutic approach.
    Keywords:  KCNMA1; KCNMB1; MRTFA; SRF; cancer; cell stiffness; ion channels; mechanobiology; mechanosurveillance; metastasis
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.001
  12. Cell. 2026 Jun 02. pii: S0092-8674(26)00567-2. [Epub ahead of print]
    Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense.
    Chew Chai, Eliya Sultan, Souradeep R Sarkar, Lihan Zhong, Dania Nanes Sarfati, Orly Gershoni-Yahalom, Christine Jacobs-Wagner, Hawa Racine Thiam, Benyamin Rosental, Bo Wang.
      Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells-T cells, natural killer cells, and neutrophils. Here, we identify "ruptoblasts," a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, "ruptosis," triggered by activin, a multifunctional hormone acting as an inflammatory cytokine. Excessive activin-induced through protein injection, genetic chimerism, or bacterial infection-initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating nearby cells, bacteria, and even mammalian cells within minutes. Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions. Mechanistically distinct from known cytotoxic and cell death mechanisms, the explosive nature of ruptosis relies on endoplasmic reticulum (ER)-derived calcium and cytoskeleton-dependent signal amplification. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.
    Keywords:  activin signaling; cell death/destruction; cytotoxicity; evolution of immune system; extreme cell biology; genetic chimeras; glandular/secretory cell types; hormonal surveillance; planarian
    DOI:  https://doi.org/10.1016/j.cell.2026.05.008
  13. Nature. 2026 Jun 02.
    Bang! Exploding immune cells splatter potent toxins everywhere.
    Amanda Heidt.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-01766-4
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