bims-nakice 2026-06-21 papers

bims-nakice

Biomed News

on Natural killer cells

Issue of 2026–06–21
ten papers selected by
Santosh Phuyal, Oslo Universitetssykehus

Recent advances in bispecific natural killer cell engagers for cancer immunotherapy.
BAP1 loss impairs IFN-γ signaling and enhances NK cell-mediated cytotoxicity in myeloid leukemia.
Interleukin-12 induces rapid STAT4/DDX5-dependent remodeling of RNA polymerase II occupancy in NK cells.
Chemical priming potentiates mesothelin-targeting chimeric antigen receptor-engineered NK-92 antitumor activity by improving tumor trafficking and cytotoxic killing dynamics.
Can natural killer cells cure leukemia?
TFPI2 promotes NK cell-mediated glioblastoma killing through adhesion and checkpoint control.
Bispecific CAR T and CAR NK cells in dual-threat immunotherapy: opportunities and challenges.
Research progress on tumor extracellular matrix stiffness and immunosuppression.
CD38+ NK cells: novel players in immunoregulation.
Protocol update to: Protocol for rapid manipulation of mitochondrial morphology in living cells using inducible counter mitochondrial morphology.

Immunotherapy. 2026 Jun 19. 1-21

Recent advances in bispecific natural killer cell engagers for cancer immunotherapy.

Mousa Thalji, Yago Nieto.

  Natural killer (NK) cells are innate cytotoxic lymphocytes capable of eliminating malignant cells independently of major histocompatibility complex (MHC) - restricted antigen recognition. This makes them particularly valuable in tumors that evade adaptive immune surveillance through MHC antigen loss or impaired processing. However, tumor-intrinsic immune evasion mechanisms and suppressive tumor microenvironments frequently impair endogenous NK cell activity, limiting the effectiveness of nontargeted autologous NK cell-based approaches.Bispecific and multispecific NK cell engagers (NKCEs) have emerged as promising immunotherapeutics designed to redirect NK cells toward tumor-associated antigens while delivering potent activating signals. These engineered molecules typically engage activating NK receptors (e.g. CD16a, NKG2D, or NKp46) to promote immune synapse formation and antigen-specific cytotoxicity. Advances in molecular engineering have enabled the development of multispecific platforms that integrate dual tumor antigen targeting, multireceptor activation, and cytokine support - particularly interleukin-15-, to enhance NK cell persistence, expansion, and functional durability.This review highlights progress in NKCE design, preclinical efficacy, and early clinical translation, while addressing safety considerations, mechanisms of resistance, and rational combination strategies, such as with adoptive NK cell therapies and checkpoint inhibitors. Collectively, NKCEs represent versatile, drug-like immunotherapies with the potential to overcome key limitations of monoclonal antibody and T cell - based therapies.

Keywords:  Allogeneic NK cell therapy; Bispecific and multispecific antibodies; Natural killer cells; Tumor microenvironment; antibody-dependent cellular cytotoxicity; bispecific NK-cell engagers; cancer immunotherapy

DOI:  https://doi.org/10.1080/1750743X.2026.2688683
Cancer Immunol Immunother. 2026 Jun 15. pii: 171. [Epub ahead of print]75(6):

BAP1 loss impairs IFN-γ signaling and enhances NK cell-mediated cytotoxicity in myeloid leukemia.

Chiara Badami, Erna Islamagic, Linnea Blomén, Frida Svensson, Theebiga Kathirkamanathan, Kristoffer Hellstrand, Elin Bernson, Fredrik B Thorén.

  Natural killer (NK) cells recognize and eliminate malignant cells through multiple receptor-ligand interactions. To uncover genetic determinants of the susceptibility of myeloid leukemia cells to NK cell cytotoxicity, we analyzed several genome-wide CRISPR screens. Among recurrent hits, the BRCA1-associated protein 1 (BAP1) gene emerged as a key factor protecting K562 leukemic cells from NK cell-mediated killing. Using BAP1 knockout (KO) models, we found that loss of BAP1 alone did not alter NK cell sensitivity. However, upon interferon-γ (IFN-γ) stimulation, BAP1 KO K562 cells exhibited reduced HLA class I induction, triggered enhanced NK cell degranulation, and showed increased sensitivity to NK cell-mediated cytotoxicity compared with wild-type cells. Further experiments revealed that BAP1-deficient cells displayed reduced expression of the IFN-γ receptor 1 (IFN-γ-R1). BAP1 knockdown across multiple myeloid leukemia cell lines selectively decreased HLA-E and IFN-γ-R1 expression in ASXL1-mutant backgrounds. These findings suggest that BAP1 may contribute to the regulation of IFN-γ responsiveness and immune evasion in myeloid leukemia.

Keywords:   BAP1 ; CRISPR/Cas9; HLA-I; IFN-γ; NK cells

DOI:  https://doi.org/10.1007/s00262-026-04453-5
J Exp Med. 2026 Aug 03. pii: e20250995. [Epub ahead of print]223(8):

Interleukin-12 induces rapid STAT4/DDX5-dependent remodeling of RNA polymerase II occupancy in NK cells.

Hyunu Kim, Simon Grassmann, Wilfred Wong, Nicholas M Adams, Yuka Kanno, John J O'Shea, Christina S Leslie, Inez Rogatsky, Joseph C Sun.

Natural killer (NK) cells are innate lymphocytes that rapidly respond to inflammatory cytokines during infection, but the mechanisms underlying such swift responses remain incompletely understood. Here, we investigated the RNA polymerase II (Pol II) dynamics during rapid cytokine-induced activation in NK cells. Brief exposure to the proinflammatory cytokine interleukin-12 (IL-12) elicited rapid, genome-wide redistribution of Pol II within minutes, with increased promoter-proximal Pol II pausing at effector loci including Ifng. This IL-12-induced Pol II reorganization was mediated by the transcription factor STAT4. We further identified the RNA helicase DDX5 as a STAT4 interaction partner required for optimal IFN-γ production and appropriate modulation of Pol II occupancy following IL-12 stimulation. Together, these findings identify STAT4/DDX5-mediated regulation of Pol II as a critical mechanism enabling the rapid responsiveness of NK cells to proinflammatory cytokines.

DOI: https://doi.org/10.1084/jem.20250995
Front Immunol. 2026 ;17 1860442

Chemical priming potentiates mesothelin-targeting chimeric antigen receptor-engineered NK-92 antitumor activity by improving tumor trafficking and cytotoxic killing dynamics.

Ki Seo Ryu, Hail Park, Eunchong Maeng, Jun-Yeon Lim, Duck Cho, Seung Hee Choi, Kyung-Soon Park.

   Introduction: Chimeric antigen receptor-engineered natural killer (CAR-NK) cells have emerged as a promising strategy for cancer immunotherapy; however, their efficacy against solid tumors remains limited by inefficient tumor trafficking and impaired cytotoxic function within the tumor microenvironment. Here, we investigated whether a non-genetic chemical priming strategy could pre-arm CAR-NK cells and enhance their migratory and cytotoxic functions.
Methods: Based on our previous findings that transient exposure to 25 kDa branched polyethylenimine (25KbPEI) induces a primed phenotype, mesothelin-targeting CAR-NK-92 cells were chemically primed and evaluated for migration, cytotoxicity, killing dynamics, perforin accumulation, cytokine production, and in vivo antitumor efficacy in a SKOV3 xenograft model.
Results: Chemical priming significantly enhanced cytotoxicity and degranulation against ovarian cancer cells without compromising cell viability. Primed CAR-NK cells showed increased CCR7 expression and improved tumor-directed migration. Live-cell imaging further revealed accelerated target engagement and shortened killing time, indicating enhanced cytotoxic kinetics. In addition, chemical priming increased perforin accumulation and IFN-γ production. In the SKOV3 xenograft model, primed CAR-NK cells achieved superior tumor control and increased intratumoral infiltration compared with non-primed CAR-NK cells, while maintaining a favorable safety profile.
Discussion: Collectively, these findings demonstrate that chemical priming enhances CAR-NK cell function and provides a promising non-genetic strategy to improve CAR-NK cell activity against solid tumor models.

Keywords:  25 kDa branched polyethylenimine; chemical priming; chimeric antigen receptor-engineered natural killer cells; mesothelin; ovarian cancer; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2026.1860442
Leukemia. 2026 Jun 15.

Can natural killer cells cure leukemia?

Frank Cichocki, Martin Felices, Anders W Matson, Madeline J Lee, Jeffrey S Miller.

DOI: https://doi.org/10.1038/s41375-026-02992-5
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2529973123

TFPI2 promotes NK cell-mediated glioblastoma killing through adhesion and checkpoint control.

Dongpeng Zheng, Fengqi Li, Zhuang Zhang, Yunyi Dong, Xuebin Zhang, Xueren Li, Jingyue Yang, Shouchun Peng, Budong Chen, Shupeng Sun, Zichuan Liu, Xin Mu.

  Immune-mediated killing triggers dynamic transcriptional adaptations in tumor cells that can reciprocally regulate the cytolytic process. Unraveling such feedback mechanisms is crucial for advancing cancer immunotherapy. Here, we identified tissue factor pathway inhibitor 2 (TFPI2) as a central node in natural killer (NK)-glioblastoma cross talk. Using transcriptomic and functional approaches, we demonstrated that NK cell attack induces TFPI2 expression in glioblastoma cells via IL1β- and TNFα-driven activation of NFκB signaling. TFPI2 not only restrains tumor proliferation by suppressing the POU2F2-CCND1 axis but also enhances NK cytotoxicity through two complementary mechanisms: It supports optimal ICAM1 expression to promote NK-tumor adhesion, and it selectively represses the immune checkpoint molecule SIGLEC15, restoring NK cell effector function. In vivo, loss of TFPI2 accelerates glioblastoma progression and abrogates the efficacy of adoptive NK cell therapy in a context-dependent manner; the functionality is likely restricted to tumors retaining the capacity for TFPI2 induction upon inflammatory stimuli. Our findings identified the TFPI2-ICAM1 and TFPI2-SIGLEC15 axes as conditional regulators of immune-tumor adhesion and checkpoint control, supporting TFPI2 as a candidate therapeutic target for a subset of glioblastomas amenable to inflammatory reprogramming.

Keywords:  ICAM1; NK; TFPI2; glioblastoma

DOI:  https://doi.org/10.1073/pnas.2529973123
Mol Biol Rep. 2026 Jun 19. pii: 963. [Epub ahead of print]53(1):

Bispecific CAR T and CAR NK cells in dual-threat immunotherapy: opportunities and challenges.

Ali Shahin Baher, Aya Khalid, Anahita Ganjalikhani Hakemi, Armita Ganjalikhani Hakemi, Mojdeh Soltani, Zohreh Saltanatpour, Andrey A Zamyatnin, Alessandro Parodi, Mazdak Ganjalikhani Hakemi.

  Antigen escape and intratumoral heterogeneity remain major barriers to durable responses in chimeric antigen receptor (CAR)-based cancer immunotherapies. While single-antigen CAR-T cell therapies have achieved notable success in hematologic malignancies, relapse driven by antigen loss, lineage plasticity, and tumor evolution remains common, and efficacy in solid tumors is limited. Similar antigen-dependent limitations are also observed in other targeted immunotherapies, including bispecific antibodies, underscoring the broader challenge of achieving durable immune control. To address these challenges, bispecific and combinatorial CAR strategies have emerged to broaden antigen coverage, enhance tumor selectivity, and reduce immune evasion. This review examines the biological mechanisms underlying antigen escape and critically evaluates dual-targeting CAR architectures, including tandem CARs, dual-CAR systems, logic-gated designs, and inhibitory CARs. We distinguish between mechanistic rationale and clinically validated benefit, highlighting the heterogeneity of outcomes across studies and the limited evidence supporting consistent superiority over optimized monospecific approaches. We summarize preclinical and clinical evidence supporting bispecific CAR-T strategies, particularly in B-cell malignancies, while discussing challenges related to toxicity, manufacturing complexity, and translational scalability. We further evaluate CAR-engineered natural killer (CAR-NK) cells as a complementary platform. Their innate cytotoxicity, favorable safety profile, and compatibility with allogeneic manufacturing offer important translational advantages, although limitations in persistence, tumor infiltration, and clinical validation remain. Finally, we position CAR-based therapies within the evolving immunotherapy landscape, emphasizing therapeutic sequencing, combination strategies, potential cross-resistance, and the need to align CAR design and platform selection with tumor-specific patterns of antigen expression and immune escape.

Keywords:  Bispecific CAR; CAR NK Cell; CAR T cell; Immunotherapy; TanCAR; iCAR

DOI:  https://doi.org/10.1007/s11033-026-12144-8
Front Immunol. 2026 ;17 1852616

Research progress on tumor extracellular matrix stiffness and immunosuppression.

Fei Wu, Po Zhang, Weichi Wu, Tian Hou, Xiaobing Jiang, Tao Huang.

  Tumor matrix stiffness, a pivotal physical attribute of the tumor microenvironment, has evolved from a passive physical barrier to an active immunoregulatory platform, profoundly impacting the initiation and effector phases of anti-tumor immune responses. This review systematically elaborates on the dual mechanisms that drive immunosuppression. Directly, stiffness attenuates T-cell and natural killer (NK) cell functions by activating pathways such as Yes-associated protein (YAP)/Transcriptional co-activator with PDZ-binding motif (TAZ) and Piezo-type mechanosensitive ion channel component 1 (Piezo1). It also drives the polarization of macrophages and dendritic cells towards immunosuppressive phenotypes. Indirectly, stiffness fosters an immune escape ecosystem by persistently activating cancer-associated fibroblasts, inducing tumor cell epithelial-mesenchymal transition, and upregulating immune checkpoints. Consequently, strategies such as enzymatic degradation, targeting mechanotransduction pathways, employing anti-fibrotic drugs, and developing intelligent combination therapies have emerged, aiming to soften tumors and reverse immunosuppression. Clinical studies confirm that high expression of the mechanosignaling hub Yes-associated protein 1 (YAP1) is associated with resistance to immunotherapy. In the future, integrating mechanobiology, immunometabolism, and smart materials to develop precise multimodal combination strategies holds promise for reversing the "cold tumor" microenvironment and opening new avenues to overcome immunotherapy resistance in solid tumors.

Keywords:  combination therapy; extracellular matrix stiffness; immunosuppression; mechanotransduction; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1852616
Front Immunol. 2026 ;17 1757958

CD38+ NK cells: novel players in immunoregulation.

Xiaotian Chang, Kehua Fang.

  CD38 is a transmembrane protein and ectoenzyme that mainly degrades nicotinamide adenine dinucleotide (NAD+). Studies have revealed increased numbers of CD38-expressing NK (CD3-CD38+CD56+) cells in many diseases. CD38+ NK cell proportions in the peripheral blood and synovial fluid are increased in patients with rheumatoid arthritis (RA), and these cells produce high levels of interferon-γ (IFN-γ) and low levels of transforming growth factor-β (TGF-β), suppressing the differentiation of CD4+ T cells to regulatory T cells (Tregs) to disrupt immune tolerance. CD38+ NK cell proportions in the peripheral blood and tumor tissues are also increased in patients with colorectal cancer (CRC). However, CD38+ NK cells produce low levels of IFN-γ and NAD+ and high levels of TGF-β and adenosine (ADO) and can promote Treg differentiation and macrophage polarization to tumor-associated macrophages (TAMs) to interrupt immune surveillance. CD38+ NK cells were not detected in CD38-KO tumor-bearing mice, and their xenograft tumors grew slowly. Furthermore, the expression of heat shock 70-kDa protein 1B (HSPA1B), a known tumor suppressor, was decreased in CD38+ NK cells from CRC patients but increased in the NK subset from RA patients. HSPA1B can suppress the signaling activity of NF-κB, a regulator of proinflammatory cytokine production. CD38 and CD16 cooperate on the NK cell membrane; most CD38+ NK cells are CD38+CD16+ NK cells that can suppress Treg differentiation. The proportion of CD38+CD16- NK cells among CD38+ NK cells in the peripheral blood was increased in patients with CRC or other tumors. The above results suggest that CD38+CD16+ and CD38+CD16- NK cells have opposing regulatory effects on CD16, HSPA1B and NF-κB signaling and cytokine secretion, leading to opposing effects on immune balance. This review provides a reference for understanding disrupted immune tolerance and surveillance, though the evidence is preliminary.

Keywords:  CD16; CD38; CD38+ NK cells; NK cells; immune surveillance; immune tolerance; regulatory T cells (Tregs); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3389/fimmu.2026.1757958
STAR Protoc. 2026 Jun 16. pii: S2666-1667(26)00288-1. [Epub ahead of print]7(3): 104635

Protocol update to: Protocol for rapid manipulation of mitochondrial morphology in living cells using inducible counter mitochondrial morphology.

Mayuko Kano, Naoko Onodera, Tomoto Ura, Satone Tanigaki, Teppei Nishino, Takafumi Miyamoto.

  Disruption of mitochondrial morphology occurs during various diseases, but the biological significance is not entirely clear. Here, we describe a detailed step-by-step protocol for a chemically inducible dimerization (CID) system-based synthetic protein device, termed inducible counter mitochondrial morphology (iCMM). This system allows artificial manipulation of mitochondrial morphology on a timescale of minutes in living mammalian cells. We also describe an AI-assisted image processing approach. For complete details on the use and execution of this protocol, please refer to Miyamoto et al.1 This protocol provides an updated version of the method described by Miyamoto et al.2.

Keywords:  Cell Biology; Microscopy; Systems biology

DOI:  https://doi.org/10.1016/j.xpro.2026.104635