bims-nakice 2026-10-04 papers

Issue of 2026–10–04
seven papers selected by
Santosh Phuyal, Oslo Universitetssykehus

bioRxiv. 2026 Sep 22. pii: 2026.09.16.752157. [Epub ahead of print]

The Histone Methyltransferase KMT2D promotes Natural Killer cell effector molecule release.

Katelynn R Kazane, Jeong Hyun Ji, Georgia R Lill, Sebastian Zolog, Christian G Bustillos, David Hsieh, Evelyn Hernandez-Almonte, Luis A Pedroza, Maureen A Su, Jordan S Orange, Timothy E O'Sullivan.

Natural Killer (NK) cells eliminate virally infected and cancerous cells by secreting cytotoxic granules and pro-inflammatory cytokines. However, the epigenetic mechanisms that coordinate these processes in human NK cells remain poorly understood. We identified two NK deficiency (NKD) patients with mutations in the histone methyltransferase KMT2D that demonstrated impaired cytotoxicity and degranulation. CRISPR-mediated KMT2D deletion or introduction of a patient-specific mutation in healthy human NK cells was sufficient to inhibit effector functions. NK cell-specific KMT2D deletion in mice resulted in defective NK cell degranulation and IFN-γ production, increasing mortality following MCMV infection. KMT2D loss reduced H3K4me1 deposition, associated with decreased levels of RAB3D. RAB3D-deficient human NK cells reduced the release of GZMB and IFN-γ, without impacting intracellular levels. Thus, KMT2D acts as a conserved epigenetic regulator of mature NK cell functions, promoting rapid effector molecule release.
HIGHLIGHTS: Mutations in KMT2D are associated with human NKD.KMT2D is required for NK cell cytotoxicity and degranulation.Loss of KMT2D in mouse NK cells increases susceptibility to MCMV infection.KMT2D regulates RAB3D to enhance the release of effector molecules.

DOI: https://doi.org/10.64898/2026.09.16.752157

Methods Mol Biol. 2027 ;3087 45-52

Natural Killer Cells and Innate Lymphoid Cells Immunoprofiling.

Christelle Piperoglou, Frédéric Vély.

Phenotyping of natural killer (NK) cells by flow cytometry allows a detailed analysis of their functional diversity and activation status. This multiparametric approach assesses the expression of activating or inhibitory receptors and detects markers of maturation or exhaustion. It is crucial for understanding the role of NK cells in the immune response, particularly against infections and tumor cells. This phenotyping also allows us to monitor the effects of immunomodulatory treatments and to identify prognostic or predictive biomarkers in different clinical contexts.

Keywords: Flow cytometry; Immunoprofling; NK cells

DOI: https://doi.org/10.1007/978-1-0716-5607-5_4

Front Immunol. 2026 ;17 1887148

Fibrinogen depletion prevents non-dissociable cell aggregates of feeder-derived NK cell products.

Jiaoqi Wu, Jianhua Chen, Mingzhu Victoria Huang, Caihua Huang, Wenyi Lee, Jian Wang, Qi Liu, Shuo Tian, Wenlin Huang.

Introduction: Natural killer cells, as critical components of the innate immune system, have shown a promising potential in cancer immunotherapy. Currently, irradiated genetically modified feeder cells are widely used to produce large quantities of highly cytotoxic NK cells. However, it is frequently overlooked that NK cell products prepared in this way tend to form non-dissociable and macroscopic aggregates during storage and transportation, posing a significant challenge in clinical applications. The formation of cell aggregates not only compromises cell yield and quality but also raises concerns for vascular occlusion or unexpected immune-related toxicity upon infusion.
Methods: To address this issue, we systematically investigated key factors contributing to aggregate formation throughout the NK cell manufacturing process. Primary NK cells isolated from cord blood or peripheral blood were expanded using feeder cells. We evaluated the impact of harvesting parameters (centrifugal force, final cell concentration, filtration pore size, and human serum albumin concentration), anticoagulant supplementation, feeder cells, and plasma fibrinogen content on aggregate formation. Aggregate formation was monitored and quantified microscopically post-formulation. Meanwhile, NK cell quality attributes, including cell apoptosis, purity, proliferation and cytotoxic function, were assessed by cell counter and flow cytometry to confirm the quality of NK cell products.
Results: Our findings suggest that the coexistence of feeder cells and fibrinogen in the culture medium jointly induces aggregation in the final NK cell product. Replacing autologous plasma with a fibrinogen-free serum substitute can effectively prevent the aggregation, without impairing NK cell expansion fold, phenotypic stability, viability, or cytotoxic potency.
Conclusions: In summary, our study unveils the phenomenon and mechanism of cell aggregation in feeder-derived NK cell products, and establishes an optimized protocol for NK cell manufacturing, which supports the clinical feasibility of feeder cell-derived NK cell therapies.

Keywords: cell aggregation; feeder cells; fibrinogen; natural killer cells; serum substitute

DOI: https://doi.org/10.3389/fimmu.2026.1887148

Cancer Discov. 2026 Sep 29.

Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks.

Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0509

FEBS J. 2026 Sep 28.

The role of organelles as mechanotransducers.

Simran Rawal, Rituraj Marwaha, Tamal Das.

Mechanobiology examines how physical forces influence cellular structure and function. Traditionally, mechanotransduction has been attributed to plasma membrane receptors, focal adhesions, and the cytoskeleton. However, emerging evidence highlights intracellular organelles as active contributors to mechanosensing and force transduction. Organelles such as the endoplasmic reticulum, nucleus, Golgi apparatus, mitochondria, and endolysosomal system possess distinct structural and biophysical properties that enable them to detect and respond to both external forces such as extracellular matrix stiffness and shear stresses and internal forces such as actomyosin contractility. This review summarizes the mechanobiological roles of major organelles, focusing on their cytoskeletal interactions, mechanosensitive channels, signaling pathways, and force-induced morphological adaptations. We also discuss inter-organelle communication under mechanical stress, including ER-mitochondria contact sites and Golgi-ER trafficking, particularly in processes such as cell migration. Additionally, we highlight recent advances in experimental and analytical approaches, including organelle-targeted Flipper-TR tension probes, optical tweezers, optogenetic force perturbation systems, and integrated single-cell omics that enable quantitative interrogation of mechanical properties and responses at subcellular resolution. Collectively, these insights position organelle mechanobiology as a critical frontier for understanding development and diseases such as cancer, fibrosis, and neurodegeneration.

Keywords: cell migration; endoplasmic reticulum; mechanobiology; mechanotransduction; organelles

DOI: https://doi.org/10.1111/febs.70739

Nature. 2026 Sep 30.

GPCR antagonism via rewiring of receptor trafficking and degradation.

Kaitlin Rhee, Lawrence Shue, Akimasa Adachi, Pengwei Sun, James Osei-Owusu, Dingjingyu Zhou, Aoxing Cheng, Yi Ran Xu, Qingyue Li, Apoorva Baluapuri, Edward P Harvey, Karen Adelman, Meredith A Skiba, Bianxiao Cui, Jun R Huh, Andrew C Kruse, Xin Zhou.

G-protein-coupled receptors (GPCRs) represent one of the most important yet incompletely addressed classes of therapeutic targets1. Here we report a strategy for functional GPCR antagonism through bispecific antibody-mediated endocytosis and lysosomal degradation. GPCR-TfR1 targeting chimeras (GTACs) achieve potent and selective downregulation of multiple GPCRs, including BILF1, RXFP1 and CCR6-viral, cancer and immune targets that have been difficult to drug2-4. GTACs lead to complete inhibition of receptor signalling, including constitutive signalling, with more than one to two orders of magnitude greater potency than conventional antibody antagonists. Using protein engineering and multicolour live-cell imaging, we establish a context-dependent degrader design and explain the cellular mechanisms, with broad relevance for degrader technology. The GTAC platform establishes induced endocytosis and rewiring protein trafficking as a model for therapeutic GPCR modulation.

DOI: https://doi.org/10.1038/s41586-026-11088-0