bims-nakice 2026-08-02 papers

bims-nakice

Biomed News

on Natural killer cells

Issue of 2026–08–02
nine papers selected by
Santosh Phuyal, Oslo Universitetssykehus

NKp44 recognition of platelet-derived growth factor D enhances the cytolytic activity of natural killer cells.
HDAC6 orchestrates NK cell maturation and antitumor immunity.
ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity.
Tumor-derived ITGB3 shapes a primed but functionally constrained NK cell state in breast cancer through HLA-E-NKG2A signaling.
Depletion of IL-10 in CAR-NK cells augments reprogramming of the tumor microenvironment and ameliorates therapeutic efficacy.
Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells.
Combinatorial therapy with resveratrol sensitizes glioblastoma to NKG2D CAR-T cells.
What's your name, immune cell?
Protocol for optogenetic stimulation of cells under physical confinement.

J Immunol. 2026 Jul 10. pii: vkag204. [Epub ahead of print]215(7):

NKp44 recognition of platelet-derived growth factor D enhances the cytolytic activity of natural killer cells.

Alexander J Sedgwick, Md Abdullah Al Kamran Khan, Nazanin Ghazanfari, Theo Mantamadiotis, Alexandra J Corbett, Julian P Vivian, Alexander David Barrow.

  Natural killer (NK) cells are cytotoxic innate lymphoid cells that play a critical role in tumor surveillance by releasing proinflammatory cytokines and cytotoxic granules. NKp44 is an activating receptor that promotes NK cell secretion of TNF and IFN-γ upon engaging platelet-derived growth factor D (PDGF-DD), a ligand frequently overexpressed in aggressive malignancies, such as glioblastoma (GBM). However, whether NKp44-mediated recognition of PDGF-DD can directly enhance NK cell cytotoxicity against tumor cells remains unclear. Here we investigated the effect of PDGF-DD stimulation on NK cell cytotoxicity by analyzing the activity of cytotoxic transcriptional programs and cytolytic function of human NK cells in flow cytometry-based cytotoxicity assays. We demonstrate that PDGF-DD stimulation of NKp44 activates a procytotoxic transcriptional program and secretion of key cytotoxic effectors, including granzyme B, perforin, and Fas ligand. This response significantly enhanced NK cell-mediated cytotoxicity of GBM cell lines (T98G, U87, LN229 and A172) and HEK 293T cells, but not the NK-sensitive K562 cell line. Furthermore, the negation of PDGF-DD-mediated cytotoxicity and lytic granule secretion upon blockade and genetic ablation of NKp44 reveal that PDGF-DD augmentation of NK cell tumoricidal activity is tumor-type specific and reliant upon NKp44. Our data highlight a novel mechanism by which NK cells can detect soluble components of the tumor secretome, expanding the paradigm of NK cell activation beyond classical cell-surface interactions.

Keywords:  NK cells; NKp44; cancer immune surveillance; cytotoxicity; platelet-derived growth factor

DOI:  https://doi.org/10.1093/jimmun/vkag204
J Immunother Cancer. 2026 Jul 27. pii: e015167. [Epub ahead of print]14(7):

HDAC6 orchestrates NK cell maturation and antitumor immunity.

Wenwen Yang, Panpan Tian, Xiaowei Guo, Miaomiao Ding, Rong Xiao, Zhuanchang Wu, Xuetian Yue, Chunyang Li, Lifen Gao, Jun Zhou, Chun-Hong Ma, Xueen Li, Jianping Wang, Xiaohong Liang.

   BACKGROUND: Natural killer (NK) cells act as the host's first line of immunosurveillance, and their maturation and effector functions are finely regulated by multiple factors. Although histone deacetylase (HDAC) inhibition has been reported to impair NK cell viability and/or antitumor effects, the specific HDAC member involved and the underlying mechanisms remain unclear.
METHODS: We analyzed the expression of HDAC family members during NK cell activation and in tumor-infiltrating NK cells. Genetic approaches, including Hdac6 knockout, knockdown, and overexpression, were used to evaluate its role in NK cell proliferation, maturation, and effector function. Mechanistic studies examined protein acetylation status, chaperone activity, and IL-15-STAT5 signaling. Functional relevance was assessed using NK cell adoptive transfer models and interleukin (IL)-15 combination treatment in tumor settings.
RESULTS: HDAC6 was the most significantly upregulated HDAC member on NK cell activation, whereas its expression was reduced in tumor-infiltrating NK cells and correlated with poor patient survival. Hdac6 deficiency markedly impaired NK cell proliferation, maturation, and effector functions, while Hdac6 overexpression showed a promoting effect. Mechanistically, loss of Hdac6 led to the hyperacetylation of HSP90, which in turn destroyed its chaperone activity for phosphorylated STAT5 and blocked the transduction of the IL-15 signaling pathway indispensable for NK cell maturation and effector function. Translationally, HDAC6 overexpression not only obviously improved tumor suppression of transferred NK cells, but also synergized with IL-15 treatment to further boost NK cell antitumor efficacy.
CONCLUSION: HDAC6 was identified as a critical regulator of NK cell biology through strengthening the IL-15/STAT5 pathway and may serve as a potential target for improving NK cell function.

Keywords:  Natural killer - NK

DOI:  https://doi.org/10.1136/jitc-2026-015167
bioRxiv. 2026 Jul 17. pii: 2026.07.12.738073. [Epub ahead of print]

ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity.

Yeara Jo, Alexandros Karampatzakis, Seung Won Lee, Alice Peng, Zaina Ghouri, Monsserratt Moya, Elizabeth Andrews, Harrison Sudholz, Chenyu Zhang, Berna Bou Tayeh, Alejandro N Medina, Jiucheng Ding, Robert A Saxton, Ziyang Zhang, Yang Shi, Hideho Okada, David H Raulet.

Natural Killer (NK) cell desensitization induced by persistent stimulation limits durable antitumor immunity, yet the molecular mechanisms governing this dysfunctional state remain poorly defined. To identify conserved regulators of NK cell desensitization, we performed comparative transcriptomic analyses across multiple murine models of persistent activation and dysfunction. This approach defined a shared transcriptional program of desensitization and identified Itpkb to be upregulated across multiple distinct contexts. Genetic and pharmacological inhibition of ITPKB enhanced degranulation, cytokine production, and cytotoxicity in both murine and human NK cells under multiple desensitization settings. Mechanistically, ITPKB regulated signaling downstream of persistent activation through the IP 3 /IP 4 axis, limiting calcium mobilization and NFAT-dependent transcriptional responses in desensitized NK cells. Furthermore, inhibition or deletion of ITPKB enhanced NK-cell mediated tumor control in vivo and improved the efficacy of adoptively transferred CAR-NK cells, underscoring the translational potential of targeting this pathway. Together, these findings identify ITPKB as a cell-intrinsic regulator of NK cell desensitization and support targeting the IP 3 /IP 4 signaling axis to enhance NK cell-mediated antitumor immunity.

DOI: https://doi.org/10.64898/2026.07.12.738073
Mol Biol Rep. 2026 Jul 27. pii: 1268. [Epub ahead of print]53(1):

Tumor-derived ITGB3 shapes a primed but functionally constrained NK cell state in breast cancer through HLA-E-NKG2A signaling.

Kunqin Wang, Xinyue Bao, Jun Yan, Jiarui Xu, Chenghan Ju, Ruijie Cao, Qi Sun.

   BACKGROUND: Natural killer (NK) cells are vital for anti-tumor immunity, yet their effector functions are frequently constrained within the tumor microenvironment. Integrin β3 (ITGB3) has been implicated in breast cancer progression and stemness, but whether ITGB3 expression in malignant cells influences NK cell states and contributes to immune evasion remains unclear.
METHODS: Single-cell RNA sequencing data were utilized to profile the transcriptomic and metabolic divergence of NK cells between ITGB3⁺ and ITGB3⁻ tumor microenvironments. Cell-cell communication and pseudotime trajectory analyses were performed to identify key signaling axes. The SCIPAC framework was employed to map single-cell subsets to the bulk TCGA-BRCA cohort for clinical correlation. The mechanistic findings were validated through in vitro co-culture assays and NKG2A blocking experiments using MDA-MB-231 and BT-474 cell lines.
RESULTS: NK cells associated with ITGB3+ tumor microenvironments displayed enhanced cytotoxic and inflammatory transcriptional programs, together with metabolic remodeling and stronger clinical associations with advanced TNM stages. Cell-cell communication analysis revealed intensified predicted interactions between ITGB3+ malignant cells and NK cells, with enrichment of MHC-I-related signaling and HLA-E-KLRC1/KLRC2 interactions. KLRC1 encodes the inhibitory receptor NKG2A, whereas KLRC2 encodes the activating receptor NKG2C. Therefore, these inferred interactions do not by themselves define the net functional direction of HLA-E signaling. Although KLRC2 was transcriptionally enriched in NK cells from the ITGB3+ tumor microenvironment, NKG2A blockade reversed ITGB3-associated suppression of NK-derived IFN-γ secretion, supporting a functional contribution of the inhibitory NKG2A branch.
CONCLUSIONS: ITGB3 expression in malignant cells is associated with a primed but functionally constrained NK cell state in breast cancer. Increased malignant-cell HLA-E expression and restoration of IFN-γ production following NKG2A blockade support a functional contribution of the inhibitory NKG2A branch, without excluding concurrent activating signaling through NKG2C.

Keywords:  Breast cancer; HLA-E; Integrin β3; NKG2A; Natural killer cell; Single-cell analysis

DOI:  https://doi.org/10.1007/s11033-026-12497-0
Mol Ther Oncol. 2026 Sep 17. 34(3): 201285

Depletion of IL-10 in CAR-NK cells augments reprogramming of the tumor microenvironment and ameliorates therapeutic efficacy.

Anja Löwe, Jasmin Röder, Aline Häcker, Anita Bhatti, Margarete Mijatovic, Nina Müller, Malena Schnieder, Anne Kiefer, Ines Kühnel, Torsten Tonn, Manuel Kaulich, Stefan Stein, Congcong Zhang, Andreas Weigert, Winfried S Wels.

  The ErbB2 (HER2)-specific CAR-engineered natural killer (NK) cell line NK-92/5.28.z is under investigation in a phase I clinical trial in glioblastoma patients. In preclinical studies, these cells demonstrated potent CAR-mediated cytotoxicity and stimulated endogenous antitumor immunity in immunocompetent animals. Pro-inflammatory cytokines can contribute to the CAR-NK cells' immunomodulatory activity, but this may be attenuated by immunosuppressive IL-10 that is also produced in substantial amounts by activated NK-92/5.28.z cells. To prevent IL-10 secretion, we modified the CAR-NK cells to express an intracellular anti-IL-10 antibody, which trapped IL-10 within the endoplasmic reticulum. This did not affect proliferation, phenotype, or cytotoxicity of the resulting NK-92/5.28.z/anti-IL10ER cells but strengthened their ability to mediate maturation of co-cultured dendritic cells and prevented M2-polarization of co-cultured macrophages induced by unmodified CAR-NK cells. In a syngeneic murine glioblastoma model, NK-92/5.28.z/anti-IL10ER cells exhibited enhanced antitumor activity and favored a pro-inflammatory tumor microenvironment characterized by reduced infiltration of IL-10-responsive immunosuppressive cell types. Our findings demonstrate that inhibiting IL-10 secretion improves the therapeutic potential of CAR-engineered NK-92 cells, suggesting this approach as a promising avenue for clinical translation.

Keywords:  ErbB2; HER2; IL-10; NK-92; chimeric antigen receptor; intracellular antibody; natural killer cells

DOI:  https://doi.org/10.1016/j.omton.2026.201285
Immunity. 2026 Jul 28. pii: S1074-7613(26)00276-1. [Epub ahead of print]

Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells.

Yassmin A Elbanna, Maria Tello-Lafoz, Aliya Holland, Ye Zhang, Chengyuan Li, Seema Amin, Zhenghan Wang, Jun-Goo Kwak, Alexandrina Yakimov, Anastasiia Vaska, Esther Lee, Myra Dada, Samuel Vayner, Sarah M Duquette, Young Hun Kim, Jahkwaun Budhai, Ning Fan, Erik Ladewig, Tejus A Bale, Benjamin Y Winer, Kenny K H Yu, Joan Massagué, Christina Leslie, Jungwoo Lee, Ori Barzilai, Scott R Manalis, Morgan Huse.

  Metastatic microenvironments vary widely not only in their biochemical composition but also in their mechanical properties. Here, we examined how the mechanical rigidity of the metastatic niche affects metastases seeding and the local efficacy of antitumor immunosurveillance. Cancer cells stiffened in response to increasing environmental rigidity, a biophysical change that mechanically sensitized them to killing by cytotoxic lymphocytes. In immunodeficient mice, rigidity sensing by cancer cells yielded robust bone colonization, accompanied by marked stiffening of the cancer cells themselves. Conversely, in immunocompetent hosts, stiffer cancer cells were selectively eliminated, and bone metastasis was suppressed. In patients, metastatic cell stiffness was associated directly with environmental rigidity and inversely with immune infiltration. Expression of Spp1, encoding the secreted glycoprotein osteopontin, defined a subset of cancer cells that expanded in the bone, and deletion of Spp1 limited environmentally induced cancer cell stiffening, bone colonization, and immune vulnerability. Thus, environmental mechanosensing regulates both metastases seeding and antitumor immunity, providing an immunological basis for metastatic site selection.

Keywords:  NK cell; bone; cytotoxic T cell; immunosurveillance; lung; mechanobiology; metastasis; metastatic site selection; osteopontin; stiffness

DOI:  https://doi.org/10.1016/j.immuni.2026.06.025
Front Immunol. 2026 ;17 1831927

Combinatorial therapy with resveratrol sensitizes glioblastoma to NKG2D CAR-T cells.

Wei Liang, Yexiao Tang, Muhammad Auwal Saliu, Mansur Dabai Salisu, Cuimei Chen, Zhiming Xu, Shu Xu, Maoxuan Liu, Xiaochun Wan.

  Chimeric antigen receptor T-cell (CAR-T) therapies have shown potential in clinical trials for glioblastoma, yet treatment responses vary due to heterogeneous antigen expression and post-treatment immune escape. NKG2D-based CAR-T cells have exhibited a favorable safety profile in patients with hematologic malignancies and demonstrated potent antitumor activity in xenograft models, including those of glioblastoma. Nevertheless, glioma cells could evade immune recognition by downregulating or proteolytically shedding NKG2D ligands. To enhance the efficacy of NKG2D CAR-T therapy, we investigated its combination with preclinical agents capable of penetrating the blood-brain barrier that could upregulate NKG2D ligands on glioma cells. Our study revealed that resveratrol (RSV), a bioactive polyphenol, significantly increased the surface expression of NKG2D ligands on glioblastoma cells. RSV pretreatment sensitized these cells to NKG2D CAR-T-mediated killing in vitro. Additionally, the combination of RSV with NKG2D CAR-T cells demonstrated potent antitumor activity in vivo. Mechanistically, RSV potentially induced NKG2D ligand expression via activation of the p53 signaling pathway. These preclinical findings identify RSV as a promising pharmacological adjuvant that enhances NKG2D CAR-T efficacy in glioblastoma, supporting further translational and clinical evaluation of this combinatory approach.

Keywords:  NKG2D; car-t; combination therapy; glioblastoma; resveratrol

DOI:  https://doi.org/10.3389/fimmu.2026.1831927
Nat Methods. 2026 Jul 27.

What's your name, immune cell?

Vivien Marx.

DOI: https://doi.org/10.1038/s41592-026-03171-1
STAR Protoc. 2026 Jul 30. pii: S2666-1667(26)00407-7. [Epub ahead of print]7(3): 104754

Protocol for optogenetic stimulation of cells under physical confinement.

Qinling Yuan, Alice Amitrano, Debanik Choudhury, Konstantinos Konstantopoulos.

  Optogenetic approaches enable spatiotemporal control of signaling proteins, yet their integration with microfluidic assays to study confined cell migration remains challenging. Herein, we present a protocol for the optogenetic activation of PI3K/Akt signaling in confined cells. We detail procedures for applying stimulation to induce localized Akt activation at the cell's leading edge. This protocol enables real-time manipulation of subcellular signaling dynamics during confined migration. For additional information on the use of this protocol, please refer to Lee et al.1.

Keywords:  Biophysics; Biotechnology and bioengineering; Cancer; Cell Biology

DOI:  https://doi.org/10.1016/j.xpro.2026.104754