bims-nakice 2026-07-12 papers

bims-nakice

Biomed News

on Natural killer cells

Issue of 2026–07–12
ten papers selected by
Santosh Phuyal, Oslo Universitetssykehus

ADAM17 blockade restores natural killer cell antibody-dependent cytotoxicity against human immunodeficiency virus-1.
Multifunctional-engineered NK cells overcome tumor immunosuppression by combining PD-L1 and HLA-E targeting and endogenous IL15 production.
From single cell analysis to 3D micro physiological systems: microfluidic tools integrating cancer cell targets for delineating natural killer cell biology.
ETV4 enhances glycolysis to suppress NK-cell cytotoxicity in the immune microenvironment of colon cancer.
Rewiring cellular immunotherapy: From CAR evolution to circuit innovations across diseases.
Tumor immune cell targeting chimeras reprogram tumor-associated macrophages.
Celldetective, an AI-enhanced image analysis tool for unraveling dynamic cell interactions.
CD137 in cancer therapy - bench to bedside.
Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.
Nascent extracellular matrix: the missing piece in hydrogel design.

Virol J. 2026 Jul 06.

ADAM17 blockade restores natural killer cell antibody-dependent cytotoxicity against human immunodeficiency virus-1.

Sho Sugawara, Stephanie Jost, Griffin Woolley, R Keith Reeves.

  Natural killer (NK) cells are critical innate effector cells against human immunodeficiency virus type 1 (HIV-1) transmission and pathogenesis. Among the diverse NK cell functions, antibody-dependent cellular cytotoxicity (ADCC) is the most critical for HIV-1 control. Nevertheless, multiple reports have demonstrated dysfunctional NK cell activity in people living with HIV-1 (PLWH), including impaired ADCC. As a putative mechanism, CD16 signaling activation in PLWH is perturbed via ADAM17-mediated CD16 downregulation, and ADAM17 blockade can reverse CD16 downregulation in PLWH NK cells. However, the link between elevated ADAM17 function and diminished HIV-1-specific NK cell ADCC has remained unclear. Thus, to fill this knowledge gap, we tested whether ADAM17 perturbation can restore HIV-1-specific NK cell ADCC. We demonstrated that inhibition of ADAM17 can restore HIV-1-specific ADCC by recovering surface CD16 expression. Furthermore, we observed that PLWH NK cells experience impaired ADCC associated with ADAM17 elevation. Altogether, we found that ADAM17 blockade can restore impaired NK cell ADCC against HIV-1, and this approach could be applied to further advance NK cell-based immunotherapeutics toward an HIV-1 cure. These findings establish ADAM17 as a tractable checkpoint to enhance Fc‑effector responses and support the integration of ADAM17 targeting into NK‑cell-based HIV cure strategies.

Keywords:  ADCC; HIV; Natural killer cell

DOI:  https://doi.org/10.1186/s12985-026-03223-0
Signal Transduct Target Ther. 2026 Jul 10. pii: 269. [Epub ahead of print]11(1):

Multifunctional-engineered NK cells overcome tumor immunosuppression by combining PD-L1 and HLA-E targeting and endogenous IL15 production.

Piera Filomena Fiore, Sergio Forcelloni, Lorenzo Moretta, Maria Rita Assenza, Paola Orecchia, Maria Teresa Bilotta, Markus Machwirth, Ted Shpati, Lokossou William Sanvi, Dorothee Haas, Simone Vitozzi, Manuela Giansanti, Francesca Nazio, Nicola Tumino, Ignazio Caruana, Paola Vacca.

The immunosuppressive tumor microenvironment (TME) poses a significant challenge to effective cancer immunotherapy, as it enables tumor escape through redundant checkpoint pathways, metabolic constraints, and direct inhibition of effector cells. To overcome these barriers, we developed a next-generation NK cell platform using a tri-cistronic retroviral vector that enhances NK cell activation, recruitment, survival, and metabolic fitness. Pan-cancer transcriptomic analyses reveal consistent co-expression of PD-L1 and HLA-E across tumors, which correlates with immune infiltration accompanied by strong immunosuppression, highlighting these molecules as key targets for immune evasion. To improve NK cell recruitment, activation, cytolytic function, survival, and metabolic fitness in the TME, we developed a next-generation NK cell platform using a tri-cistronic retroviral vector that encodes an extracellular PD-1 domain (exPD1) fused to the intracellular portion of NKG2D with the costimulatory molecule 4-1BB, and expressing soluble IL15 and NKG2A single-chain variable fragments (scFv). Thus, the exPD1 allows the recognition of cells expressing PD-L1, while the intracellular costimulatory signaling transforms the inhibitory interaction PD-1/PD-L1 into an activating one. This strategy effectively targets PD-L1-positive tumor cells and induces de novo PD-L1 expression in otherwise negative tumors. To further enhance anti-tumor activity, we incorporated a module encoding soluble NKG2A-scFv to mask the NKG2A receptor on NK cells and hinder NKG2A/HLA-E inhibitory interaction. Additionally, we improved NK cell survival and expansion by delivering controlled low doses of IL15, which prevents NK cell exhaustion and extends their presence in vivo. This integrated strategy may provide a novel, ready-to-use allogenic mature NK cell therapy that could overcome checkpoint-mediated inhibition, metabolic suppression, and immune escape, offering a promising model for treating high-risk and treatment-resistant tumors.

DOI: https://doi.org/10.1038/s41392-026-02827-w
Microsyst Nanoeng. 2026 Jul 06. pii: 255. [Epub ahead of print]12(1):

From single cell analysis to 3D micro physiological systems: microfluidic tools integrating cancer cell targets for delineating natural killer cell biology.

Maria V Hangad, Heqing Ma, Sam K P Kung, Francis Lin.

Natural killer cell is a critical cell type in our immune system. Its therapeutic potential in the development of novel cancer immunotherapy has been emerging. Microfluidic technologies capable of manipulating small volumes of fluid through microchannels are emerging tools for advancing our knowledge of natural killer cell biology. However, the rationale behind microfluidic device design, material choice, and the precise engineering of in vitro microenvironments has yet to be systematically assessed through the lens of complex NK cell biology using cancer cells as targets for activation. This comprehensive review assesses microfluidic technologies designed for the study of NK cell phenotype/function at a single cell level, migration dynamics in the presence or absence of biochemical cues, natural killer-target cell interactions, and observation of sophisticated cellular behavior (infiltration/cytotoxicity) in multi-factorial complex microenvironments. Step by step advances in device complexity such as the integration of acellular hydrogels or multicellular co-culture systems highlight the emerging need for higher resolution analysis of natural killer cell properties at the single cell, tissue, and organ levels. The progression of microfluidic technologies for advancing knowledge of natural killer (NK) cell biological mechanisms within the last twenty years. Figure was generated using BioRender.

DOI: https://doi.org/10.1038/s41378-026-01351-9
Biochim Biophys Acta Gen Subj. 2026 Jul 10. pii: S0304-4165(26)00078-4. [Epub ahead of print] 130978

ETV4 enhances glycolysis to suppress NK-cell cytotoxicity in the immune microenvironment of colon cancer.

Zixing Zhang, Pengfei Wang, Yingchuan Chen, Jian Wang, Weifeng Yang, Wenquan Ou, Xing Huang, Yao Wei, Xinwei Zhao, Xiaohua Wu.

  Immune evasion in colon cancer (CC) is largely driven by the functional suppression of NK cells, yet the specific regulatory role of ETV4 in this process remains poorly defined. We first analyzed ETV4 expression levels in CC through bioinformatics prediction and qPCR validation. A tumor-NK cell co-culture system was established to assess NK cell cytotoxicity and glycolytic metabolic profiles, which were examined via Seahorse and lactate/glucose assays. A nude mouse xenograft model combined with the glycolysis inhibitor 2-DG was applied for validation. ETV4 was significantly upregulated in CC tissues, and its high expression correlated with adverse clinical prognosis and decreased intratumoral NK cell infiltration. ETV4 potentiated tumor glycolysis by upregulating the expression of key glycolytic enzymes LDHA and PDK1, which consequently impairs NK cell cytotoxicity and the production of NK cell effector molecules. Glycolysis inhibition reversed this NK-cell suppression. ChIP-qPCR and dual-luciferase reporter assays validated that ETV4 transcriptionally activated LDHA. In vivo, ETV4 accelerated tumor growth via glycolysis, and this effect was blocked by 2-DG treatment. In conclusion, by transcriptionally activating LDHA, ETV4 facilitates glycolysis and thereby inhibits NK cell-mediated antitumor immunity in CC The ETV4-glycolysis axis may serve as a therapeutic target.

Keywords:  Colon cancer; ETV4; Glycolysis; NK cells

DOI:  https://doi.org/10.1016/j.bbagen.2026.130978
Biotechnol Adv. 2026 Jul 09. pii: S0734-9750(26)00186-2. [Epub ahead of print] 108980

Rewiring cellular immunotherapy: From CAR evolution to circuit innovations across diseases.

Jiayi Chen, Yaxin Cui, Keyi Du, Jiangshan Liu, Jing Xie, Simiao Wang, Zhaogang Yang.

  Chimeric antigen receptor (CAR)-based immunotherapy has evolved from early linear receptor designs into increasingly sophisticated biological signal processing systems. While conventional CAR-T cell therapies have achieved remarkable clinical success, particularly in hematologic malignancies, their broader application is constrained by limited scalability, manufacturing complexity, and treatment-related toxicities. These challenges have driven the expansion of CAR engineering beyond T cells to alternative immune cell types, including natural killer (NK) cells and macrophages, as well as the diversification of genetic delivery and control strategies. Concurrently, advances in synthetic biology have reframed CARs not merely as static receptors but as programmable immune circuits capable of integrating multiple inputs, executing logical operations, and generating context-dependent outputs. Such circuit-based designs enable precise regulation of immune activation, improved discrimination between tumor and healthy tissues, and enhanced functional persistence within heterogeneous and immunosuppressive microenvironments. In this review, we conceptualize CAR-based immunotherapy as a form of biological signal processing and systematically trace its transition from linear CAR architectures to programmable immune circuits. We summarize engineering strategies for both ex vivo and in situ reprogramming of immune cells, compare viral and nonviral gene delivery platforms, and discuss key design principles underlying circuit CARs across different disease contexts.

Keywords:  CAR-T; CAR-immune cells; Circuit CAR; Immunotherapy; synNotch CAR

DOI:  https://doi.org/10.1016/j.biotechadv.2026.108980
Nat Chem Biol. 2026 Jul 08.

Tumor immune cell targeting chimeras reprogram tumor-associated macrophages.

Mariko Morimoto, David S Roberts, Ru M Wen, Ell Handy, Eric E Peterson, Grace M Stepek, Nicholas A Till, James D Brooks, Carolyn R Bertozzi.

Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis but also a dominant cell population, with tumor-associated macrophages (TAMs) comprising up to 50% solid tumor mass. Immunotherapies such as immune checkpoint inhibitors derive efficacy from this cancer-immune interface; however, immune-related adverse events from systemic blockade remain a major challenge. To address this need for potent, tumor-specific immunotherapies, we developed tumor immune cell targeting chimeras (TICTACs) that selectively deplete immune checkpoint receptors such as SIRPα from TAM surfaces. These chimeras consist of a synthetic ligand targeting CD206, a TAM marker, conjugated to a nonblocking antibody that binds to the checkpoint receptor without inhibiting it. By engaging CD206, which constitutively recycles between the plasma membrane and early endosomes, TICTACs drive robust checkpoint degradation in CD206high macrophages, with no effect on CD206low cells. This decoupling of antibody selectivity from blocking function presents a new paradigm for tumor-specific immunotherapies.

DOI: https://doi.org/10.1038/s41589-026-02258-2
Elife. 2026 07 08. pii: RP105302. [Epub ahead of print]14

Celldetective, an AI-enhanced image analysis tool for unraveling dynamic cell interactions.

Rémy Torro, Beatriz Díaz-Bello, Dalia El Arawi, Ksenija Dervanova, Lorna Ammer, Florian Dupuy, Patrick Chames, Kheya Sengupta, Laurent Limozin.

  Analysis of multimodal and multidimensional data capturing dynamic interactions between diverse cell populations is a current challenge in bioimaging, especially in the context of immunology and immunotherapy research. Here, we introduce Celldetective, an open-source Python-based software tool designed for high-performance end-to-end analysis of image-based in vitro immune and immunotherapy assays. Celldetective is purpose-built for multicondition, 2D multi-channel time-lapse microscopy of mixed cell populations. Although it is optimised for the needs of immunology assays, it is nevertheless broadly applicable to any biological system involving interacting cell populations. The software seamlessly integrates AI-based segmentation, tracking, and automated single-cell event detection, all within an intuitive graphical interface that supports interactive visualisation, annotation, and training options. We showcase its capabilities with original datasets of single immune effector cell interactions with an activating surface mediated by bispecific antibodies and pairwise interactions in antibody-dependent cell cytotoxicity events.

Keywords:  bioimage analysis; bispecific antibody; cancer cell line; computational biology; deep learning; human; immune cells interactions; immunology; inflammation; multimodal microscopy; primary immune cells; systems biology

DOI:  https://doi.org/10.7554/eLife.105302
Immunotherapy. 2026 Jul 09. 1-17

CD137 in cancer therapy - bench to bedside.

Kathrine S Rallis, Jessica J Liegel, Alexandra Pommier, M Felicia Ciuculescu, José A Cancelas, John G Gribben, David E Avigan.

  CD137 (4-1BB; TNFRSF9) is an inducible costimulatory receptor of the tumor necrosis factor receptor (TNFR) superfamily expressed on activated CD8+ and CD4+ T-cells, natural killer cells, and dendritic cells. By reinforcing T-cell survival, expansion, and memory formation, CD137 has become an attractive target in cancer immunotherapy. Therapeutic strategies include agonistic monoclonal antibodies, bispecific molecules, and adoptive cell therapies enriched for tumor-reactive lymphocytes. Clinical-grade closed bioreactor systems feature a CD137-based enrichment platform utilizing antigen-induced CD137 upregulation to isolate and expand clinically relevant T-cell subsets. Additional innovations such as dendritic cell co-culture systems expressing CD137L and single-cell technologies that characterize highly reactive CD137+ T-cells further enhance precision and potency. Clinical trials of CD137 agonists have shown promising anti-tumor activity; however, hepatotoxicity and variable patient responses remain challenges. Recent work in non-human primate models has clarified the role of CD137 signaling in modulating alloreactivity, with implications for graft-versus-host disease. Despite ongoing barriers - including toxicity, therapeutic resistance, and limited biomarkers - CD137 remains a compelling immunologic target. Future efforts will emphasize context-specific agonism, refined cellular engineering, and multi-omic integration to improve patient selection and therapeutic design. This review summarizes CD137 biology, emerging therapeutic strategies, and translational and clinical directions.

Keywords:  CD137; bispecifics; cancer; immunotherapy; monoclonal antibodies

DOI:  https://doi.org/10.1080/1750743X.2026.2700925
Autophagy. 2026 Jul 06. 1-23

Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.

Nitish Chauhan, Ananda Guha Majumdar, Sujit Kumar Bhutia, Papiya Dey, Mahesh Subramanian, Birija Sankar Patro.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapy resistance driven by lysosome-dependent nutrient recycling, metabolic adaptation, and stress tolerance. Current lysosome targeting agents such as chloroquine (CQ)/hydroxychloroquine (HCQ) show limited efficacy due to transient activity and dose-limiting-toxicities. To overcome these limitations, we developed lysostilbenes, a new class of hybrid small molecules combining the CQ pharmacophore with lysosome-disrupting stilbene analogs. Stilbene pharmacophore is the core structural component of resveratrol. Among the synthesized hybrids, lysostilbene-4 emerged as the lead candidate, demonstrating ~30-40-fold greater cytotoxicity against PDAC cells than parent compounds, while sparing nonmalignant cells. At nanomolar concentrations, lysostilbene-4 induced rapid, irreversible lysosomal membrane permeabilization (LMP), initiating a lysosome mitochondria apoptotic cascade via CTSB (cathepsin B) release, BID cleavage, BAX activation, and caspase-mediated apoptosis. In parallel, it abrogated lysosomal recovery by significantly reducing repair, lysophagy, autophagosome maturation, and uncoupling TFEB-driven transcriptional programs from effective lysosome biogenesis. Reduced TFEB mRNA expression correlated with poor overall-survival and disease-free-survival across multiple cancer patients, with a particularly strong association in pancreatic cancer patients. Using TFEB+/+ and TFEB-/- knockout pancreatic cancer cells we establish that lysostilbene-4 exerts severe cytotoxicity by inducing persistent lysosomal-damage and disrupting autophagosome-lysosome assembly, with vulnerability further amplified in TFEB-deficient cells. This finding underscores TFEB as a key determinant of lysosomal-resilience and a potential predictive biomarker. Importantly, lysostilbene-4 was well tolerated in preclinical mouse-models at supra-therapeutic doses without systemic-toxicity. These findings position lysostilbene-4 as a first-in-class lysosome-targeting therapeutic that enforces sustained lysosomal collapse while compromising adaptive recovery-mechanisms, providing a mechanistically precise and safe strategy against PDAC.Abbreviations: ALG: autophagy-lysosome genes; AMPK: AMP-activated protein kinase; CASM: conjugation of ATG8s to single membranes; CTSB: cathepsin B; LGALS3: galectin 3; LMP: lysosomal membrane permeabilization; LS: lysostilbene; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; TCGA: The Cancer Genome Atlas; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

Keywords:  Chloroquine; dihydroxystilbene; lysophagy; lysosome repair; lysostilbene; resveratrol

DOI:  https://doi.org/10.1080/15548627.2026.2693263
Cell Biomater. 2026 Jun 16. pii: 100404. [Epub ahead of print]2(6):

Nascent extracellular matrix: the missing piece in hydrogel design.

Joshua Yu-Chung Liu, Matthew L Tan, Claudia Loebel.

  Almost every cell in vivo is surrounded by the extracellular matrix (ECM), which contributes to cell and tissue fate. Biomaterials, especially engineered hydrogels, have emerged as platforms to recreate the biochemical and mechanical properties of ECM. Yet most approaches still assume that cells directly respond to the engineered hydrogel, although there is increasing evidence that numerous cell types rapidly deposit newly synthesized (nascent) ECM (nECM). Studies have now shown that this nECM accumulates at the cell-hydrogel interface, where it also contributes to a cell's fate. In this perspective, we first highlight key studies describing the nECM as a regulator of cell fate. Next, we provide guidelines based on physicochemical principles for studying nECM through spatiotemporal mapping, mechanical/structural measurements, biochemical characterization, and functional assays. Finally, building upon existing hydrogel engineering tools, we propose chemical- and protein-engineering approaches to specifically engineer the nECM to more precisely control cell-matrix interactions.

Keywords:  Extracellular matrix; cell culture; cell-matrix interactions; hydrogel; protein engineering

DOI:  https://doi.org/10.1016/j.celbio.2026.100404