bims-nakice Biomed News
on Natural killer cells
Issue of 2026–10–11
seven papers selected by
Santosh Phuyal, Oslo Universitetssykehus
  1. From recognition to serial killing: Molecular mechanisms controlling NK-cell-mediated tumor elimination.
  2. B7-H3 expression impacts outcomes in myeloma and is targetable with an NK cell engager.
  3. Tumor-on-a-chip with single-cell microfluidics reveals distinct NK cell immunosuppression by hypoxia versus lipid accumulation.
  4. Responses to endoplasmic reticulum stress at a glance.
  5. The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.
  6. Mechanically Regulated Secretion: How Physical Forces Instruct the Secretory Pathway and Remodel the Secretome.
  7. Strategies for endoplasmic reticulum-targeted delivery systems: current design principles and trends.
  1. Biochim Biophys Acta Rev Cancer. 2026 Oct 06. pii: S0304-419X(26)00206-4. [Epub ahead of print]1881(6): 189734
    From recognition to serial killing: Molecular mechanisms controlling NK-cell-mediated tumor elimination.
    Zhaojun Pang, Yifu Liu, HanYang, RuiWang, Huimin Liu, Xuliang Wang, Shouchun Peng, Xueren Li, Shupeng Sun, Xin Mu.
      Natural killer (NK) cells are critical regulators of tumor immune surveillance and represent an important platform for cancer immunotherapy. However, the ability of NK cells to eliminate tumor cells is determined by a multistep cellular process involving signal integration, cytotoxic interface formation, effector execution, and functional maintenance. Conventional evaluation approaches, including receptor-ligand profiling, cytokine production, CD107a degranulation and endpoint cytotoxicity assays, provide valuable measurements of overall NK activity but often fail to define the specific cellular process that limits tumor-cell elimination. Here, we propose a stage-resolved framework to interpret NK-cell antitumor cytotoxicity by dividing the killing process into four interconnected functional stages: recognition and early activation, cytotoxic synapse maturation, effector delivery and death execution, and serial killing with sustained tumor control. For each stage, we summarize the molecular mechanisms that regulate signal initiation, receptor organization, cytoskeletal remodeling, granule trafficking, target-cell death sensitivity, and metabolic adaptation. We further discuss how tumor-intrinsic resistance programs and therapeutic interventions influence individual stages of the NK-cell killing process. This framework provides a mechanistic perspective for understanding heterogeneous NK-cell dysfunction by localizing functional constraints within the cytotoxic cascade rather than relying solely on global activity measurements. By linking molecular mechanisms with stage-specific functional readouts, this approach may facilitate the identification of actionable targets, interpretation of therapeutic responses, and rational development of combination strategies in NK-cell-based cancer immunotherapy.
    Keywords:  NK cell cytotoxicity; Stage-based assessment; Tumor immune escape
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189734
  2. Blood Immunol Cell Ther. 2026 Sep;pii: 100069. [Epub ahead of print]2(3):
    B7-H3 expression impacts outcomes in myeloma and is targetable with an NK cell engager.
    Aimee M Merino, Bartosz Grzywacz, Hayden Hamsher, Young Vue, Hazel Reilly, Benjamin Miller, Petra Krhovska, Colleen Forster, Zachary Davis, Laura Bendzick, Megan Weivoda, Neha Sharma, Anders Narum, Ryan Shanley, Martin Felices, Nicholas A Zorko, Evren Alici, Jeffrey S Miller.
      B7-H3 acts as a checkpoint inhibitor, influences the tumor microenvironment, and is necessary for osteoclast (OC) development. Given its dual roles in promoting cancer survival and bone breakdown, we looked at its expression pattern in >200 multiple myeloma (MM) patients and association with cytogenetic abnormalities and outcomes. We found that most newly diagnosed patients had B7-H3+ plasma cells or stroma regardless of cytogenetic risk and expression on plasma cells increased with subsequent relapses. In marrow aspirates and core biopsies we identified B7-H3+ myeloid derived suppressor cells (MDSC) and (OC). We found that high B7-H3 expression was associated with pathologic fractures, bone lesions, and worse progression free survival (PFS). To confirm the utility of B7-H3 as a target in MM, we tested a tri-specific killer engager (TriKE) that binds CD16 on natural killer (NK) cells and B7-H3 while also delivering a recombinant IL-15 molecule to promote NK cell activity. The B7-H3 TriKE restored the ability of patient-derived NK cells to recognize and kill MM and enhanced NK cell-mediated killing of tumor, MDSC, OCs, and fibroblasts. These data suggest that targeting B7-H3 may positively impact outcomes and prevent the development of new bone lesions. In addition to its ability to directly target MM and immunosuppressive cells in the tumor microenvironment, the B7-H3 TriKE improved cytokine secretion and polyfunctionality of NK cells in a single cell assay. These findings advance our understanding of B7-H3's role in MM pathogenesis and validate the use of the B7-H3 TriKE to improve therapeutic outcomes in MM.
    Keywords:  B7-H3; MDSC; TriKE; bone lesion; multiple myeloma; natural killer engager; osteoclast; pathologic fracture
    DOI:  https://doi.org/10.1016/j.bict.2026.100069
  3. Lab Chip. 2026 Oct 05.
    Tumor-on-a-chip with single-cell microfluidics reveals distinct NK cell immunosuppression by hypoxia versus lipid accumulation.
    Aoling Wang, Yunting Wang, Xiahe Han, Qiurui Chen, Wu Liu.
      Immunosuppression induced by metabolic stress within the solid tumor microenvironment (TME) critically limits the efficacy of cancer immunotherapies. Here, we develop a tumor microenvironment-on-a-chip (TMoC) platform integrated with single-cell microfluidic analysis to precisely model both hypoxic and lipid-enriched conditions commonly found in solid tumors. Utilizing this system, we elucidate the distinct effects of these two metabolic stressors on natural killer (NK) cell function. Hypoxia broadly suppresses NK cell cytotoxicity and downregulates multiple functional molecules. In contrast, lipid accumulation exerts a selective inhibitory effect, reducing granzyme B and IL-10 expression while relatively preserving IFN-γ mRNA expression. Single-cell analysis reveals stress-induced functional heterogeneity and secretory synergy among NK cells. Notably, we identified a relatively high-IFN-γ-secreting subpopulation retained under lipid-rich conditions despite an overall reduction in IFN-γ secretion at the single-cell level. Furthermore, single-cell pairing assays dissociate global killing efficacy from killing kinetics, revealing that hypoxia and lipid accumulation impair NK cells through distinct kinetic modes. Using the TMoC platform to evaluate combination therapies targeting both hypoxia and lipid metabolism, we show that dual intervention synergistically restores NK cell cytolytic function. The platform demonstrates superior screening sensitivity compared to conventional in vitro models. Collectively, this work highlights the potential of integrating engineered microphysiological systems with single-cell analysis to decipher complex TME interactions and guide the development of immunotherapeutic strategies.
    DOI:  https://doi.org/10.1039/d6lc00668j
  4. J Cell Sci. 2026 Oct 01. pii: jcs264817. [Epub ahead of print]139(19):
    Responses to endoplasmic reticulum stress at a glance.
    Eric Chevet, Céline Philippe, Tony Avril, Elodie Lafont.
      The endoplasmic reticulum (ER) is the gateway to the eukaryotic protein secretory pathway. Beyond its role in protein biogenesis, it is central to Ca2+ homeostasis and lipid biosynthesis. This organelle, which can constitute more than 50% of the cellular membranes in secretory cells, is highly plastic and must adjust to intracellular or extracellular challenges to ensure proper protein secretion. ER stress, resulting from challenges such as accumulation, misfolding or aggregation of proteins or from disrupted ER lipid composition, can deleteriously affect cell function. Thus, the ER has evolved adaptive mechanisms that lead to cellular reprogramming to adjust its capacity to handle stress, including the unfolded protein response (UPR), which engages various ER quality control systems, protein degradation pathways and ER-organelle contacts. If this succeeds, the cell survives; but if it fails, cell death mechanisms are triggered. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on ER stress and control of the UPR in mammalian cells, highlighting aspects that require further attention. We also discuss recent insights that must be considered to better capture the full understanding of the ability of the ER to adjust to biological variation.
    Keywords:  Contact sites; Endoplasmic reticulum; Proteostasis; UPR; Unfolded protein response
    DOI:  https://doi.org/10.1242/jcs.264817
  5. J Cell Mol Med. 2026 Oct;30(19): e71380
    The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.
    Yew Hwang Chee, Matthieu Moncan, Eileen Reidy, Adrienne M Gorman, Afshin Samali.
      The tumour microenvironment (TME) comprises a dynamic network of structural, cellular, and signalling components that interact to influence tumour development. Immune cells play a key role in recognizing and eliminating cancer cells through detection of tumour-derived membrane and secreted proteins processed in the endoplasmic reticulum (ER). These ER-matured proteins on target cells act as critical communication signals, coordinating immune responses against tumour cells. However, during tumorigenesis, accumulation of unfolded or misfolded proteins in the ER of the cancer cells triggers the unfolded protein response (UPR), a transcriptional program that alleviates proteotoxic stress by reshaping the cancer cell proteome and secretome, thereby promoting survival. Activation of UPR disrupts intercellular communication and ultimately impairs immune-mediated tumour clearance. Understanding this crosstalk could inform the development of therapeutics targeting UPR-driven immune modulation. This review discusses how UPR-signalling modulates tumour-immune cell interactions within the TME.
    Keywords:  antigen presentation; anti‐tumour immunity; cancer therapy; endoplasmic reticulum (ER) stress; immune modulation; secretome; tumour microenvironment (TME)
    DOI:  https://doi.org/10.1111/jcmm.71380
  6. Adv Sci (Weinh). 2026 Oct 06. e78102
    Mechanically Regulated Secretion: How Physical Forces Instruct the Secretory Pathway and Remodel the Secretome.
    Domenico Russo, Seetharaman Parashuraman, Maria Luigia Maresca, Angela Francesca Dinoi, Alessia Calcagnì, Riccardo Rizzo.
      Cells do not secrete in a vacuum: they continuously interpret mechanical and chemical stimuli. This "cell sociology" drives collective behaviors and communication networks, allowing cells to process information from their surroundings. Over the past decade, growing evidence shows that all major secretory organelles are responsive to mechanical cues, overturning the view of secretion as a purely biochemical process. Cues like extracellular matrix (ECM) stiffness, cell shape, membrane tension, and tissue deformation dynamically tune trafficking at every step, remodeling endoplasmic reticulum (ER) exit sites, reshaping Golgi architecture, redirecting sorting at the trans-Golgi network (TGN), repositioning endolysosomes, and controlling exosome release. This mechanical control operates through complementary transcriptional and post-translational mechanisms, including GTPase activation, kinase cascades, cytoskeletal tension, and lipid remodeling, enabling rapid organelle reconfiguration. A mechano-secretory feedback loop exists: the physical microenvironment reorganizes the secretory pathway, and the resulting secretome changes reshape ECM composition and tissue mechanics. While supporting physiological homeostasis, this loop dysregulation drives fibrosis, cancer progression, and immune dysfunction. In this review, we integrate recent major findings to provide a coherent framework for understanding how mechanical forces reshape the secretory pathway and influence tissue function and disease.
    Keywords:  ECM; disease; fibrosis; mechanical cues; mechanosensing; mechanotransduction; secretory pathway; trafficking
    DOI:  https://doi.org/10.1002/advs.78102
  7. Expert Opin Drug Deliv. 2026 Oct 09.
    Strategies for endoplasmic reticulum-targeted delivery systems: current design principles and trends.
    Hana Cho, Han Chang Kang.
       INTRODUCTION: The endoplasmic reticulum (ER) governs proteostasis, lipid biosynthesis, calcium signaling, stress responses, and antigen presentation, making it an attractive yet challenging intracellular target for therapeutic delivery.
    AREAS COVERED: PubMed and Google Scholar were searched, with ER-targeting literature limited to January 2024-August 2026; no date limit was applied to foundational ER biology. We compare small-molecule motifs, peptide signals, biomimetic membranes, lipid-based formulations, physicochemical trafficking cues, and enzyme-instructed self-assembly, with particular attention to stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), palmitic-acid-mediated trafficking, shape-engineered exosome-membrane-coated nanorods, ER-tropic polymers, and retrograde sorting combined with ER retention. A four-level evidence framework for ER-targeting claims is proposed, alongside cargo-specific design, safety, manufacturability, and translational considerations.
    EXPERT OPINION: Among recent strategies, SABER has the most complete evidence for a defined protein-ligand ER docking interaction, although the docking protein is itself pharmacologically active and dynamically trafficked, which constrains both generalizability and the interpretation of ER residence. Near-term progress is more likely to come from matching validated targeting motifs to appropriate cargos and quantifying the entire delivery pathway than from increasingly elaborate nanocarrier designs. Clinically viable systems will require non-perturbing ligands, human-relevant validation models, biodegradable formulations, and biomarkers predictive of ER exposure and therapeutic response.
    Keywords:  Endoplasmic reticulum stress; Organelle-targeted drug delivery; endoplasmic reticulum targeting; endoplasmic reticulum targeting evidence; intracellular trafficking; subcellular drug delivery
    DOI:  https://doi.org/10.1080/17425247.2026.2748107
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