bims-nakice 2026-07-05 papers

bims-nakice

Biomed News

on Natural killer cells

Issue of 2026–07–05
ten papers selected by
Santosh Phuyal, Oslo Universitetssykehus

LFA-1 mechanical dose controls DNAM-1 signalling and perforin polarization in NK cells.
Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma.
PCGF1-mediated bivalent promoter remodeling enables NK cell immune evasion in non-small cell lung cancer.
Coordinated Roles of T Cells and Natural Killer Cells in Tumor Immunity.
EGFRxCD16 bispecific antibodies orchestrate superior NK cell-mediated lysis of ovarian cancer and NSCLC cell lines in combination with oncolytic viruses.
Natural killer cell-derived extracellular vesicles reprogram cellular human immunity to enhance tumor cytotoxicity.
GPC3 chimeric antigen receptor (CAR)-NK cells combined with Enoblituzumab enhance the anti-tumor efficacy against hepatocellular carcinoma.
Biomechanical signaling of cytoskeleton and membrane reorganization in tumor immune chemotactic migration.
Lipid droplets as stress-buffering organelles in cancer cell homeostasis.
Generating Tumor Organoid Cultures from the Lung Adenocarcinoma Cell Line.

RSC Adv. 2026 Jul 02.

LFA-1 mechanical dose controls DNAM-1 signalling and perforin polarization in NK cells.

Seong Ho Kim, Micah Yang, Isaac T S Li.

Natural killer (NK) cells are essential effectors of the innate immune system, playing a vital role in controlling viral infections and tumour progression by limiting their spread and reducing tissue damage. NK cell activity is tightly regulated by a balance of activating and inhibitory receptors on their surface, with extensive research focusing on how receptor expression levels affect NK cell function. However, the mechanical properties of lymphocyte function-associated antigen-1 (LFA-1) are still not well understood. Specifically, how LFA-1 mediates mechanical forces in NK cells has not been fully elucidated. To investigate this, we quantified and modulated LFA-1 tension in NK cells using DNA-based tension gauge tethers (TGTs) functionalized with intercellular adhesion molecule-1 (ICAM-1). By using multiplexed TGTs that combine unzip and shear geometries while maintaining a constant molecular density, we enabled precise control over the mechanical dosage delivered via LFA-1-mediated adhesion by modulating the proportion of ligand-receptor bonds above a defined force threshold. This method allowed fine-tuning of LFA-1-mediated mechanotransduction and its downstream effects, including LFA-1/DNAM-1 colocalization and perforin polarization toward the cell-substrate interface. Our findings demonstrate that high-tension LFA-1/ICAM-1 interactions are associated with enhanced perforin polarization and receptor organization at the immune synapse, consistent with increased NK cell activation.

DOI: https://doi.org/10.1039/d6ra02527g
Nat Commun. 2026 Jun 30.

Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma.

Shi Yong Neo, Yu Mei, Joni Chong, Kang Yi Lee, Jyue Yuan Lim, Menaka P Rajapakse, Timothy Wai Ho Shuen, Junzhe Zhao, Le Tong, Tasneem Kajiji, Hui Shi Cheong, Charis Toh, Zhen Wei Neo, Li Yen Chong, Wei Lin Tang, Nicholas Ang, Alicia Tay, Xinsong Chen, Hartman Johan, Shanshan Wu Howland, Joe Poh Sheng Yeong, Subhra Kumar Biswas, Elaine Lim, Hanry Yu, Shengli Xu, Han Chong Toh, Haiyan Liu, Kong-Peng Lam.

Despite promising development as emerging "off-the-shelf" therapeutics against cancer, natural killer (NK) cells still faced considerable challenges in the solid tumor microenvironment (TME), including poor penetrance and immuno-suppression. Here, we employ spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). Orthogonal analysis of human and mouse HCC tumors indicate that the expression of NR4A1, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons, and better disease-free survival in HCC. Conditional ablation of Nr4a1 in NK cells perturbs their homeostasis and accelerates tumor progression in multiple tumor models. Conversely, the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhances their anti-tumor functions. Mechanistically, downstream functional assays confirm that Nur77 activation attenuates CD36 expression in NK cells and confers resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlight the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against HCC.

DOI: https://doi.org/10.1038/s41467-026-75027-3
Cell Death Dis. 2026 Jun 30.

PCGF1-mediated bivalent promoter remodeling enables NK cell immune evasion in non-small cell lung cancer.

Hui Zhou, Hechun Lin, Yiru Kong, Hongyu Pan, Wenjun Chai, Lei Sun, Yu Wang, Mengxi Ge, Xiaoyu Ji, Rongrong Yao, Qing Wang, Tao Liu, Mingxia Yan, Xiaohua Liang, Hong Li, Jing Li, Xinli Zhou.

Precise regulation of the activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development but is frequently disrupted in cancer. Among the polycomb group (PCGF) family members, which are key components of polycomb repressive complex 1 (PRC1), PCGF1 emerged as the factor most strongly associated with poor prognosis in non-small cell lung cancer (NSCLC) based on analyses of The Cancer Genome Atlas (TCGA) cohort. In lung cancer cells, PCGF1 upregulation enhanced the deposition of H2AK119ub and H3K27me3 at chromatin. These depositions inhibit the cytokine-cytokine receptor interaction pathway, especially CCL5, CXCL10, CD40, and FAS. Single-cell RNA sequencing further indicated that PCGF1 acts as a negative regulator of natural killer (NK) cell effector function. When NK cell-derived cytokines attempted to activate the cytokine-cytokine receptor interaction pathway in tumor cells, this repressive chromatin state attenuated pathway activation. Consequently, reduced expression of these genes weakened NK cell recruitment and cytotoxic responses. Collectively, this study uncovers a previously unrecognized mechanism by which PCGF1-driven disruption of bivalent promoter balance silences immune signaling cascades, enabling tumor cells to evade NK cell-mediated immunity in NSCLC. These findings highlight bivalent chromatin as a critical regulatory node in tumor immune escape and establish PCGF1 as a promising epigenetic target for immunotherapeutic intervention.PCGF1 promotes immune evasion in NSCLC by suppressing cytokine-cytokine receptor interaction pathway. Upregulation of PCGF1 in NSCLC cells enhances the deposition of the repressive histone modifications H2AK119ub and H3K27me3 while reducing the enrichment of the transcriptionally active histone modification H3K4me3 at target chromatin regions, thereby suppressing cytokine-cytokine receptor interaction pathway. This epigenetic repression reduces the expression of immune-related genes, including CCL5, CXCL10, CD40, and FAS. Consequently, tumor-cell responses to NK cell-derived cytokines are attenuated, leading to impaired NK cell recruitment and cytotoxicity. The schematic diagram was created using BioRender.

DOI: https://doi.org/10.1038/s41419-026-09003-6
Curr Cancer Drug Targets. 2026 Jun 30.

Coordinated Roles of T Cells and Natural Killer Cells in Tumor Immunity.

Ashiq Ali, Wajiha Afzal, Aisha Khatoon, Mohsan Ullah, Kaynaat Akbar, Manahil Zafar, Isra Noor.

  Both adaptive immune cells, particularly T cells, and innate lymphoid cells, such as Natural Killer (NK) cells, play critical yet complementary roles in tumor immunity. While T cells mediate antigen-specific cytotoxic responses, NK cells provide rapid, innate recognition and elimination of transformed cells, and their interplay can significantly enhance antitumor immunity, offering potential improvements in immunotherapeutic efficacy. Recent studies indicate that NK cells are essential for recruiting type 1 conventional dendritic cells (cDC1) into the tumor microenvironment, which in turn promotes the activation and expansion of tumor-specific CD8+ T cells. Conversely, activated T cells secrete interleukin-2 (IL-2), a cytokine crucial for NK cell proliferation, survival, and cytotoxic function, establishing a positive feedback loop that amplifies immune responses against malignancies. Tumors, however, exploit immune evasion mechanisms, including modulation of the activating receptor NKG2D and its ligands MICA and MICB, to escape detection by both NK and T cells. Furthermore, these lymphocytes share important inhibitory and activating receptor pairs, such as CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E, which regulate cytotoxic potential and maintain immune homeostasis. Targeting these shared checkpoints or modulating receptor-ligand interactions represents a promising strategy to overcome tumor immune evasion. By elucidating the coordinated actions of NK and T cells and their shared regulatory pathways, novel immunotherapeutic approaches can be developed to enhance antitumor responses, improve treatment efficacy, and ultimately improve clinical outcomes for cancer patients.

Keywords:  Tumor immunity; adaptive immune cells; cytokines; immune evasion mechanisms; innate lymphoid cells

DOI:  https://doi.org/10.2174/0115680096454137260622045925
Cancer Immunol Immunother. 2026 Jul 03. pii: 178. [Epub ahead of print]75(7):

EGFRxCD16 bispecific antibodies orchestrate superior NK cell-mediated lysis of ovarian cancer and NSCLC cell lines in combination with oncolytic viruses.

Sarah Gahbauer, Thomas Poiret.

  Combination therapy integrating bispecific antibody (BsAb) and oncolytic viruses (OVs) to enhance antitumor immune response offers a promising therapeutic approach in comparison with OV treatment alone. This study aims to strengthen and characterize NK cell-mediated antitumor responses using modified oncolytic viruses, i.e., ONCOS-102 and ONCOS-204 genetically engineered to express Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and the ligand of inducible T-cell co-stimulator (ICOSL), respectively, in combination with a BsAb targeting CD16 and the epidermal growth factor receptor (EGFR). Changes in phenotype, degranulation, cytokine production, and cytotoxicity of NK cells induced by combined treatment were compared with those induced by individual treatment strategies against non-small cell lung cancer, malignant melanoma, and ovarian cancer. Using flow cytometry and colorimetry-based cytotoxic assays, our results showed that EGFRxCD16 BsAb was the main variable in driving NK cells toward an activated phenotype and enhanced NK function; while the OVs alone did not demonstrate drastic impact on NK cells. Interestingly, tumor preconditioning with OVs in combination with EGFRxCD16 BsAb showed the most potent NK cytotoxicity in comparison with EGFRxCD16 BsAb alone and appeared to synergize best against ovarian and EGFRmut lung tumor cell lines. Despite differences between tumor types, our data suggest a favorable interplay between OVs, especially ONCOS-102, and EGFRxCD16 BsAb in sensitizing NK cell antitumor response in vitro. These results warrant further in vivo exploration and clinical translation of this promising combination of therapeutic modalities.

Keywords:  Bispecific antibody; CD16; EGFR; NK cells; Oncolytic virus

DOI:  https://doi.org/10.1007/s00262-026-04470-4
Mol Ther Oncol. 2026 Sep 17. 34(3): 201261

Natural killer cell-derived extracellular vesicles reprogram cellular human immunity to enhance tumor cytotoxicity.

Frederic St-Denis-Bissonnette, Karan Mediratta, Nicholas Ho, Melanie Kirkby, Andrew Stalker, Gauri Muradia, Amit Shrestha, Michele Ardolino, Seung-Hwan Lee, Dylan Burger, Arvind Mer, Lisheng Wang, Jessie R Lavoie.

  Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (EVs), which transfer molecular signals between cells and influence immune function. Although NK cell-derived EVs (NK92-EVs) have shown the ability to directly kill cancer cells, how they shape the broader human immune response has remained unclear. Here, NK92-EVs were shown to reprogram cellular human immunity to enhance tumor cytotoxicity using single-cell transcriptomics and functional cytotoxicity assays. When human peripheral blood mononuclear cells (PBMCs) from healthy and cancer patients (who exhibit systemic dysregulation) were exposed to NK92-EVs, widespread shifts in gene activity occurred across key immune populations, notably CD8+ T cells and NK cells. These changes enhanced the cells' ability to recognize and eliminate tumor targets and were consistent across all donors. Functional depletion and enrichment experiments, together with transcriptomic profiling, provide direct evidence that NK92-EV-mediated immune reprogramming enhances NK cell-driven, MHC-I-independent tumor cytotoxicity, but not for CD4+ and CD8+ T cells. This work advances understanding of immune communication and highlights NK92-EVs as promising, cell-free candidates for the next generation of cancer immunotherapies that unite potency with clinical scalability.

Keywords:  EVs; NK cells; PBMCs; TNBC; cellular reprogramming; extracellular vesicles or exosomes; immunomodulation; immunotherapy; natural killer cells; peripheral mononuclear blood cells; scRNA-seq; single-cell RNA sequencing; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.omton.2026.201261
Biochem Biophys Res Commun. 2026 Jun 25. pii: S0006-291X(26)00954-X. [Epub ahead of print]829 154190

GPC3 chimeric antigen receptor (CAR)-NK cells combined with Enoblituzumab enhance the anti-tumor efficacy against hepatocellular carcinoma.

Wen Zhuang, Guanyu Xiao, Mengyao Zhang, Jie Wang, Wenjing Tang, Yong Liang.

  Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Although CAR-NK cell therapies have shown promise in hematologic malignancies, their efficacy in solid tumors like HCC is often limited by antigen escape. Here, we investigated a dual-targeting strategy combining GPC3 CAR-NK cells with the B7H3-blocking monoclonal antibody Enoblituzumab. We confirmed GPC3 and B7H3 co-expression in HCC tissues and cell lines via database analysis and flow cytometry. GPC3 CAR-NK cells were generated from expanded human PBMC-derived NK cells. In vitro cytotoxicity against HCC cells was assessed by LDH release and real-time cell analysis, while IFN-γ secretion and CD107a degranulation were measured by ELISA and flow cytometry. In vivo antitumor efficacy was evaluated in NCG mice bearing subcutaneous Huh7 tumors. High GPC3 and B7H3 co-expression correlated with poor patient prognosis. GPC3 CAR-NK cells exhibited potent cytotoxicity against HCC cells in vitro. Enoblituzumab triggered strong killing effects against B7H3-positive tumors. Notably, the combination synergistically enhanced cytotoxicity, IFN-γ production, and CD107a degranulation compared to either monotherapy. In vivo, combination treatment significantly suppressed tumor growth without inducing weight loss or splenomegaly, demonstrating favorable efficacy and safety. Our findings demonstrate that dual targeting of GPC3 and B7H3 effectively enhances NK cell-mediated antitumor activity. This strategy leverages both CAR-mediated specificity and NK cell-intrinsic mechanisms, providing a strong rationale for developing dual-target immunotherapies to improve outcomes in HCC patients.

Keywords:  B7H3; CAR-NK cells; Dual targets; GPC3; Hepatocellular carcinoma; Synergistic effects

DOI:  https://doi.org/10.1016/j.bbrc.2026.154190
Theranostics. 2026 ;16(13): 7324-7344

Biomechanical signaling of cytoskeleton and membrane reorganization in tumor immune chemotactic migration.

Qijie Zhao, Keliang Chen, Minglu Zhou, Jing Jin.

  A prominent activity of the chemokine system is the regulation of immune cells trafficking in tumor microenvironment (TME). This elegant chemotaxis process is regulated by both chemokine receptors (CKRs) stimulation and intracellular factors, such as chemokine, actin cytoskeleton, cell adhesion molecules, membrane fluidity, metabolic reorganization that govern differences in tumor immune cells migration patterns. At the core of tumor immune cell migration and effector functions are three fundamental questions: how CKR signaling triggers morphological changes, how the interplay between actin/selectin and energy metabolism regulates force production, and how cytoskeletal signaling adapts to membrane fluidity. In this review, we discuss the potential influences of CKRs signaling of the actin/selectin cytoskeleton reorganization, membrane fluidity, force regulation, and metabolic reorganization in immune cell chemotaxis. Apparently, the activity of immune cells migration is not regulated solely by chemokine-receptors recognition, as biomechanical-metabolic signaling orchestrate is critical for migratory morphology regulation. By using current knowledge of general chemotaxis mechanisms as a framework, we hope to provide new insights into secondary changes mechanisms of cytoskeleton and morphology network in supporting the tumor immune cells migration. Unraveling the mechanisms underlying chemotaxis and coupled mechanical immune checkpoints holds immense potential for discovering novel therapeutic targets in cancer immunotherapy.

Keywords:  Actin; Chemokine receptors (CKRs); Chemotaxis; Cytoskeleton; Metabolic reprograming

DOI:  https://doi.org/10.7150/thno.134995
Commun Biol. 2026 Jun 29. pii: 868. [Epub ahead of print]9(1):

Lipid droplets as stress-buffering organelles in cancer cell homeostasis.

Ruolun Wei, Claudia K Petritsch.

Lipid droplets (LDs) are dynamic organelles that support homeostasis and shield cancer cells from stress to promote cancer cell survival, progression, and therapy escape. Here, we summarize recent findings demonstrating LD crosstalk with other organelles and the immune/stromal compartments aimed at buffering metabolic, oxidative, proteotoxic, and lipotoxic stress and stress from cancer treatment and the anti-tumor immune response. We briefly summarize current experimental approaches, including imaging, biochemical, and functional approaches, used to study LD biology. Together, these findings place LDs at the center of cancer cell homeostasis and highlight their emerging potential as translational targets in cancer therapy.

DOI: https://doi.org/10.1038/s42003-026-10566-5
J Vis Exp. 2026 Jun 12.

Generating Tumor Organoid Cultures from the Lung Adenocarcinoma Cell Line.

Xinzhou Zhao, Yuanlong He, Xinhua Lin, Bin Guo.

Here, we describe a protocol for generating Cell Line-Derived Tumor Organoids (CDTOs) from the A549 human lung adenocarcinoma cell line. The protocol involves embedding 2D-expanded A549 cells in Matrigel and maintaining them in 3D culture medium for long-term culture. Recommended seeding density of 500 cells/µL was determined to support consistent organoid formation. The resulting CDTOs were characterized by hematoxylin and eosin (H&E) staining and immunofluorescence (IF). The organoids maintained high expression of the lung adenocarcinoma markers Thyroid Transcription Factor 1 (TTF-1), adhesion protein E-Cadherin (ECAD), and cytoskeleton protein Keratin 7 (KRT7). Furthermore, tight junction protein Zona Occludens 1 (ZO-1) expression showed dysregulated polarity of tumor organoids. This protocol offers a technically straightforward, cost-effective, and purely tumorous organoid platform for lung adenocarcinoma research. Its simplicity and reproducibility also make it suitable for undergraduate laboratory teaching, where it can help students acquire fundamental 3D tumor organoid culture techniques within a limited lab schedule.

DOI: https://doi.org/10.3791/70387