bims-nakice 2026-10-25 papers

bims-nakice

Biomed News

on Natural killer cells

Issue of 2026–10–25
eight papers selected by
Santosh Phuyal, Oslo Universitetssykehus

TIM-3 Functions as an Activator of NK Cells in GBM and Can Be Upregulated by Torin-1: Implications for Exogenous NK Cell Transplantation.
eVLP-mediated CREM editing enhances cytotoxicity of bicistronic IL-15-armored CD19/BCMA dual-target CAR-NK cells.
Chemokines as regulators of CAR-T cell trafficking, function, and context-dependent tumor cell death.
Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma.
Tumor stiffness creates a ferroptotic Achilles' heel through YAP-SKP2 signaling.
Protocol for eVLP-mediated CRISPR-Cas9 and prime editing in pancreatic cancer cell lines.
Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.

Immunology. 2026 Oct 23.

TIM-3 Functions as an Activator of NK Cells in GBM and Can Be Upregulated by Torin-1: Implications for Exogenous NK Cell Transplantation.

Yuning Liu, Tram Dao, Shambhavi Borde, Diana Dinh, Sofia Lombardi, Sandra Torregrosa-Allen, Haley A Harper, Veronika Slivova, Aaron Cohen-Gadol, MacKenzie McIntosh, Bennet D Elzey, Sandro Matosevic.

  Functional dysregulation in the microenvironment of glioblastoma (GBM) fuels tumour cell proliferation at the expense of negatively reprogramming natural killer (NK) immunosurveillance. Building on our previous findings that tumour-infiltrating NK cells from GBM patients downregulate TIM-3 and that TIM-3 loss correlates with reduced cytotoxic potential, we sought to further investigate TIM-3 as a marker of functional NK cell activity. Here, we demonstrate that Torin-1, a pharmacological inhibitor of mTOR, upregulates TIM-3 expression on NK cells, sparing and enriching this functionally competent population while simultaneously suppressing GBM metabolism. Using patient data, genetic knockout models, and patient-derived orthotopic xenografts, we characterize TIM-3 as a receptor that contributes to NK cell activation and enables retention of effector function under conditions of torin1 therapy. These findings have direct implications for exogenous NK cell transplantation strategies, suggesting that TIM-3 expression status should be considered in the selection and engineering of NK cell products for adoptive transfer into GBM, and that Torin-1 preconditioning may enhance the functional competence of transplanted NK cells within the tumour microenvironment.

Keywords:  TIM‐3; glioblastoma; immunometabolism; mTor; natural killer cells

DOI:  https://doi.org/10.1111/imm.70211
Front Immunol. 2026 ;17 1976202

eVLP-mediated CREM editing enhances cytotoxicity of bicistronic IL-15-armored CD19/BCMA dual-target CAR-NK cells.

Fengqin Shang, Guanlie Li, Shiting Gong, Lijiao Zhao, Bingyu Niu, Hanyi Chen, Yuchen Fu, Lijun Zhao, Jianxun Wang, Yuanyuan Shi.

  Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising platform for cancer immunotherapy; however, optimization of CAR architecture and additional engineering strategies remain necessary to improve their functional activity. In this study, we generated CD19/BCMA dual-target CAR constructs based on tandem and bicistronic configurations with or without membrane-bound interleukin-15 (mbIL-15), and further evaluated engineered virus-like particle (eVLP)-mediated CREM editing as an additional strategy for CAR-NK cell engineering. Four CAR configurations were evaluated in primary human T and NK cells for CAR expression, cytotoxicity, cytokine production, and proliferative activity. Bicistronic CD19/BCMA CAR-mbIL-15 cells exhibited enhanced functional activity compared with corresponding tandem CAR-mbIL-15 cells, including increased tumor-cell killing and activation-associated functional responses in vitro. In a CD19/BCMA-positive leukemia xenograft model, bicistronic CD19/BCMA CAR-mbIL-15 T and NK cells reduced tumor burden, delayed disease progression, and prolonged survival. Furthermore, eVLP-mediated CREM editing achieved efficient genome modification in primary NK cells and remained compatible with subsequent CAR engineering. CREM-edited CAR-NK cells exhibited increased cytotoxic activity compared with unedited CAR-NK cells in vitro. Collectively, these findings support the development of modular CAR-NK engineering strategies integrating CAR architecture optimization, membrane-bound cytokine armoring, and transient genome engineering.

Keywords:  CAR-NK cells; CAR-T cells; CD19/BCMA dual targeting; CREM editing; IL-15 armoring; cancer immunotherapy; engineered virus-like particles; genome editing

DOI:  https://doi.org/10.3389/fimmu.2026.1976202
Front Immunol. 2026 ;17 1963794

Chemokines as regulators of CAR-T cell trafficking, function, and context-dependent tumor cell death.

Ksenia Levchuk, Alexey Petukhov, Shynggys Tursymbek, Kuanysh Seitkamal, Arailym Bertleuova, Denis Bulanin, Nikolai A Barlev.

  Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its efficacy in solid tumors remains limited by inefficient trafficking, suppressive myeloid and regulatory T-cell populations, and metabolic stress. These barriers contribute to incomplete tumor cell killing and loss of CAR-T cell function. Chemokines are usually viewed as migratory guides, but in solid tumors they also orchestrate immune cell positioning and inflammatory state. In this review, we discuss how chemokine gradients form inflammatory niches and control CAR-T-cell recruitment, intratumoral distribution, retention, and egress. We also examine how chemokine programs interact with cytokine signaling and regulated tumor cell death to shape local and potentially tissue-wide antitumor immunity, including through the release of damage-associated molecular patterns (DAMPs). Finally, we outline translational strategies that include engineered chemokines and matched chemokine receptor programs to enhance the efficacy of chemokine/cytokine-armored CAR-T cells, and related combination therapies.

Keywords:  CAR-T cells; chemokines; functional chemokine gradients; immune resistance; immunogenic cell death; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1963794
Nat Chem Biol. 2026 Oct 22.

Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.

Dina Y Bass, Ekaterina S Potekhina, Alexander V Ivanenko, Aleksandr A Moshchenko, Dmitry A Korzhenevskiy, Alexey M Nesterenko, Evgeny K Shevchenko, Anastasia E Karnaeva, Natalia F Zakirova, Alexander V Ivanov, Liubov E Shimolina, Marina V Shirmanova, Olga V Lyang, Olga I Patsap, Olga M Kudryashova, Guzel R Gazizova, Elena I Shagimardanova, Sofia S Mariasina, Vasiliy A Ivlev, Ivan Bogeski, Oleg A Gusev, Vsevolod V Belousov.

Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.

DOI: https://doi.org/10.1038/s41589-026-02350-7
J Transl Med. 2026 Jul 24. pii: 1325. [Epub ahead of print]24(1):

Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma.

Alfonso Navarro-Zapata, María Octavia De Santisteban, Rita María Regojo-Zapata, Marta Ibáñez-Navarro, Laura Clares-Villa, Marta de la Hoz, Andrea Romero, Carmen Mestre-Durán, Karima Al-Akioui Sanz, Halin Bareke, Sara Naharro, Jordi Minguillón, Lidia Pertíñez, Natalia Riestra, Mireia Masot, Carla Martín-Cortázar, Cristina Aguirre-Portolés, Cristina Ferreras, Adriana Mañas, Antonio Pérez-Martínez, Lucía Fernández Casanova.

   BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is associated with high mortality despite aggressive multimodal therapies for high-risk patients. Novel treatments such as CAR T cell therapy offer promise, yet challenges persist due to immune evasion mechanisms by tumor cells. Specifically, the interaction between the natural killer group 2D (NKG2D) receptor on cytotoxic immune cells and its ligands (NKG2DL) is critical for antitumor immunity. However, the expression of NKG2DL is tightly regulated by different means, including epigenetic mechanisms. NB cells often downregulate NKG2DL expression to evade immune control, and this reduction is associated with poorer survival and worse prognosis.
METHODS: The NKG2DL expression was assessed in a set of NB cell lines and patient-derived xenograft organoids (PDXOs) under basal conditions and following treatment with epigenetic drugs, valproic acid (VPA) and tazemetostat (TZM). NKG2D-CAR T cells were generated, and their proliferation, phenotype, cell-killing assays and cytokine production were performed in vitro. Cell-based assays were performed combining epigenetic drugs and NKG2D-CAR T cells in the different NB models.
RESULTS: Our study revealed that NKG2DL expression in NB models and patient samples exhibited considerable heterogeneity, but it was low overall. Although NKG2DL expression does not necessarily preclude susceptibility, its downregulation may compromise the cytotoxicity of NKG2D-CAR T cells. Treatment with epigenetic drugs, VPA and TZM, significantly increased NKG2DL expression and improved NKG2D-CAR T cell-mediated killing in vitro and in vivo.
CONCLUSION: This work suggests that targeting epigenetic pathways can enhance the susceptibility of NB cells to NKG2D-CAR T cell therapy, thereby providing a potential new approach to treat high-risk NB.

Keywords:  CAR T cells; Epigenetic pathways; Immunotherapy; NKG2D; Neuroblastoma

DOI:  https://doi.org/10.1186/s12967-026-08685-y
JCI Insight. 2026 Oct 22. pii: e204554. [Epub ahead of print]

Tumor stiffness creates a ferroptotic Achilles' heel through YAP-SKP2 signaling.

Emma Villares, Nico Taber, Shao-Chin Wu, Connor Amelung, Jianli Wu, Chao-Chieh Lin, Jen-Tsan Chi, Sharon Gerecht.

  Matrix stiffness is a hallmark of aggressive solid tumors and strongly associated with therapeutic resistance and poor prognosis. This mechanical barrier represents a major unmet challenge in oncology, as current strategies rarely address how matrix mechanics themselves drive treatment resistance. Here, we identified ferroptosis, an iron-dependent form of cell death, as a potential long-sought vulnerability that can be exploited to eliminate mechanically resistant tumors. Using genetic and chemical approaches, we investigated how matrix stiffness sensitizes cancer cells to ferroptosis and whether this vulnerability can be therapeutically targeted. We found that cancer cells cultured on stiff matrices were more sensitive to ferroptosis than those on soft matrices, as evidenced by reduced cell viability and elevated lipid peroxidation. Furthermore, we found that matrix stiffness induced YAP activation, which upregulated its target gene SKP2, a key mediator required for the heightened ferroptosis sensitivity observed under stiff conditions. Finally, using an injectable hydrogel system, we demonstrated that stiffened tumors were resistant to chemotherapy but remained highly susceptible to ferroptosis induction, resulting in markedly reduced tumor volume and weight. Our findings established ferroptosis as a stiffness-dependent vulnerability mediated by a YAP-SKP2 signaling axis, revealing a mechanotransductive pathway that may be leveraged to target treatment-refractory tumors.

Keywords:  Cancer; Cell biology; Cell stress; Extracellular matrix; Metabolism; Oncology

DOI:  https://doi.org/10.1172/jci.insight.204554
STAR Protoc. 2026 Oct 17. pii: S2666-1667(26)00557-5. [Epub ahead of print]7(4): 104904

Protocol for eVLP-mediated CRISPR-Cas9 and prime editing in pancreatic cancer cell lines.

Chloe Timmins-Young, Marco Cordani, Elisa Giovannetti, Despoina Aslanoglou, Alvaro Gutierrez, Eithne Costello, Mark Glenn.

  Pancreatic ductal adenocarcinoma (PDAC) cell lines resist transfection, limiting gene-editing experiments. Here, we present a protocol for delivering CRISPR-Cas9 or prime editors into PDAC cell lines using retrovirus-derived engineered virus-like particles (eVLPs). We describe steps for generating eVLPs, packaging CRISPR-Cas9 ribonucleoproteins or prime editors with engineered prime-editing guide RNAs (epegRNAs), and transducing human PDAC cells. We use the HEK3 locus and NQO1 (NAD(P)H quinone dehydrogenase 1) exon 6 as example edits and controls, respectively. This protocol adapts readily to other genomic sites.

Keywords:  Biotechnology and bioengineering; CRISPR; Cancer

DOI:  https://doi.org/10.1016/j.xpro.2026.104904
Cell. 2026 Oct 23. pii: S0092-8674(26)01208-0. [Epub ahead of print]

Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.

Hannah N Bell, Kavya Nair, Kole Tison, Peng Liao, Hongwei Lei, Marwa O El-Derany, Ayijiang Yisimayi, Haiwei Zhang, Ryan Rebernick, Weichao Wang, Yoshitaka Adachi, Cristina Castillo, Nupur K Das, Jinsu An, Vivien R Sutton, Xun Lin, Heng Lin, Xinghao Wang, Yunfei Li, Linda Vatan, Amr Aboud, Shuang Wei, Miguel Gijon, Samantha Goodwin, Yatrik M Shah, Ilona Kryczek, Joseph A Trapani, Margarida Barroso, Judy Lieberman, Weiping Zou.

  Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.

Keywords:  NK cell; T cell; ferroptosis; granzyme; immune checkpoint blockade; iron; mitochondria; perforin

DOI:  https://doi.org/10.1016/j.cell.2026.09.062