bims-nakice 2026-08-23 papers

Issue of 2026–08–23
six papers selected by
Santosh Phuyal, Oslo Universitetssykehus

Front Immunol. 2026 ;17 1895832

Oncolytic HSV1716 attenuates tumor-killing activity of infected primary NK cells.

Katharina H Susek, Dani Holla, Claire Marsal, Muhammad Kashif, Jonathan Albert, Viktoria Flore, Mari Gilljam, Maria Karvouni, Stephan Meinke, Arnika K Wagner, Colin Powers, Robert Allen, Evren Alici.

Oncolytic herpes simplex virus type-1 (HSV1)-based therapies engage innate immune responses, including natural killer (NK) cells, which are regarded as antiviral effector cells that eliminate virus-infected tumor targets. In this study, we examined interactions between the HSV1-derived oncolytic virus HSV1716 and primary human NK cells. Co-culture experiments revealed increased activation and degranulation of NK cells in response to HSV1716-infected tumor cells, despite the downregulation of ligands for NK-cell activating receptors on infected targets. Following co-culture with infected tumor cells, but not after incubation with viral inoculum alone, viral gene expression and increased viral copy numbers were detected in NK cells, indicating enhanced viral acquisition and persistence associated with target-cell contact. HSV1716-infected NK cells displayed impaired tumor cell killing ability. Single-cell sequencing analysis revealed downregulation of key NK effector genes alongside alterations in stress-response pathways in HSV1716 infected NK cells. Together, these findings demonstrate that primary human NK cells are infected by HSV1716 and undergo functional and phenotypic changes, leading to a diminished cytotoxic capacity. Given the emerging role of NK cell-based therapies in cancer, these findings may be relevant for the design and timing of oncolytic virus-based strategies in the future.

Keywords: HSV1716; cancer immunotherapy; natural killer cell; oncolytic virus; virus-carrying NK cells

DOI: https://doi.org/10.3389/fimmu.2026.1895832

Autophagy. 2026 Aug 20. 1-18

Inhibiting PIK3C3/VPS34 enhances anti-GD2 immunotherapy in neuroblastoma.

Jiawen Zhang, Xiaoming Liu, Longgui Chen, Todd D Schell, Giselle Saulnier Sholler, Vladimir Spiegelman, Yoshinori Takahashi, Hong-Gang Wang.

Anti-GD2 immunotherapy has improved survival in children with high-risk neuroblastoma, yet relapse and refractory disease remain major challenges, underscoring the need for strategies that extend therapeutic benefit. We investigated whether inhibition of PIK3C3/VPS34, a class III PtdIns3K that regulates autophagy and endosomal trafficking, could potentiate anti-GD2 therapy. Inducible PIK3C3/VPS34 knockdown induced apoptosis, impaired spheroid growth, and suppressed tumor progression. Notably, PIK3C3/VPS34 depletion enhanced anti-GD2 antibody-driven NK cell cytotoxicity and increased tumor cell-surface GD2 expression. In vivo, combined PIK3C3/VPS34 inhibition and anti-GD2 therapy achieved durable tumor suppression, which was associated with increased infiltration of NK cells and T cells, enhanced T-cell activation, reduced immunosuppressive myeloid populations, enhanced pro-inflammatory macrophage polarization, and elevated production of immune-recruiting chemokines. Pharmacological PIK3C3/VPS34 inhibition recapitulated the effects of genetic depletion, inducing neuroblastoma cell death and enhancing anti-GD2 antibody-dependent NK cell cytotoxicity in vitro. Enhanced NK cell-mediated killing was associated with marked enrichment of GD2 at the tumor cell surface. PIK3C3/VPS34 inhibition caused a disproportionate increase in surface relative to total cellular GD2 levels, while combined inhibition of PIK3C3/VPS34 and lysosomal function resulted in additional GD2 accumulation, supporting a role for endolysosomal processing in controlling GD2 abundance. Together, these findings demonstrate that PIK3C3/VPS34 inhibition enhances the efficacy of anti-GD2 immunotherapy through complementary tumor-intrinsic and immune-mediated mechanisms, including direct tumor cell killing, increased cell-surface GD2 expression, and enhanced antitumor immune responses within the tumor microenvironment, supporting PIK3C3/VPS34 inhibition as a promising therapeutic strategy for high-risk neuroblastoma.Abbreviations: ADCC: antibody-dependent cellular cytotoxicity; ANOVA: analysis of variance; BafA1: bafilomycin A1; dox: doxycycline; ELISA: enzyme-linked immunosorbent assay; FVS780: fixable viability stain 780; FACS: fluorescence-activated cell sorting; GD2: disialoganglioside 2; G-MDSCs: granulocytic myeloid-derived suppressor cells; HCQ: hydroxychloroquine; IP: intraperitoneal; MHC-I: major histocompatibility complex class I; PtdIns3K: class III phosphatidylinositol 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; shRNA: short hairpin RNA; TME: tumor microenvironment; Tregs: regulatory T cells.

Keywords: Anti-GD2 immunotherapy; GD2; VPS34; antibody-dependent cellular cytotoxicity; natural killer cells; neuroblastoma

DOI: https://doi.org/10.1080/15548627.2026.2717948

J Gen Physiol. 2026 Sep 07. pii: e202413564. [Epub ahead of print]158(5):

A ratiometric ER calcium sensor for quantitative comparisons across cell types and subcellular regions.

Ryan J Farrell, S Thomas Hennigan, Kirsten G Bredvik, Michael B Hoppa, Timothy A Brown, Timothy A Ryan.

The ER is an important regulator of Ca2+ in cells and dysregulation of ER Ca2+ homeostasis can lead to numerous pathologies. Understanding how various pharmacological and genetic perturbations of ER Ca2+ homeostasis impact cellular physiology would be facilitated by quantitative measurements of ER Ca2+ levels that allow for robust comparisons across conditions. To achieve this, we enhanced our original high dynamic range ER Ca2+ indicator, ER-GCaMP6-150, by fusing it to the HaloTag protein, which when bound to Janelia Fluor (JF) dyes creates a ratiometric ER Ca2+ probe. This probe (ER-Halo-GCaMP6-150) displayed minimal changes to the Ca2+-binding properties compared with our original ER Ca2+ probe as shown through in vitro and in cell Ca2+ calibrations. We describe a method to use this ratiometric probe for quantitative comparisons of ER Ca2+ concentrations and leverage this technique to compare ER Ca2+ levels across cell types and subcellular compartments. Using this approach, we show that the resting concentration of ER Ca2+ in primary dissociated neurons does not differ between excitatory and inhibitory subtypes nor between axonal and somatodendritic compartments. However, resting ER Ca2+ levels in neuronal somas are substantially lower than that measured in embryonic fibroblasts. The ER-Halo-GCaMP6-150 provides a robust tool to directly measure ER Ca2+ levels for studies of ER physiology across cell types and compartments.

DOI: https://doi.org/10.1085/jgp.202413564

Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073

Allosteric rewiring of mitochondrial stress signaling through Miro1.

Layla Drwesh, Julia C Fitzgerald.

In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.

DOI: https://doi.org/10.1016/j.chembiol.2026.07.011

Nat Commun. 2026 Aug 20. pii: 8736. [Epub ahead of print]17(1):

AI-enabled discovery and biochemical optimization of minibinders targeting cancer cell-surface proteins.

Experimental validation and functional optimization remain bottlenecks in AI-based protein design. We present a scalable workflow for developing AI-designed minibinders against cancer-associated surface proteins. Screening thousands of designs using mammalian cell-surface display identifies several high-affinity PD-L1 minibinders but far fewer for CD276 (B7-H3) and VTCN1 (B7-H4), highlighting substantial target dependence. Interface predicted template modeling (ipTM) scores generated by Chai-1 with ESM embeddings correlate with binding success and capture deleterious effects of interface mutations. Fluorophore-labeled AI-minibinders enable flow-cytometric staining comparable to conventional antibodies. However, when incorporated into chimeric antigen receptors (CAR), some show poor cell-surface trafficking and limited functionality. Redesign through a genetic algorithm-based diversification strategy that preserves the binding interface while changing non-binding surfaces experimentally reveals an isoelectric point (pI) window that improves CAR expression and enhances target-selective tumor cell killing. Our findings identify biochemical optimization beyond the binding interface as a critical requirement for translating AI-minibinders into functional applications.

DOI: https://doi.org/10.1038/s41467-026-76760-5

Nature. 2026 Aug 21.

Sleuth identifies dozens of studies that used the wrong antibody.

Holly Else.

Keywords: Ageing; Cancer; Immunology; Publishing

DOI: https://doi.org/10.1038/d41586-026-02352-4