bims-nakice 2026-06-28 papers

bims-nakice

Biomed News

on Natural killer cells

Issue of 2026–06–28
thirty-one papers selected by
Santosh Phuyal, Oslo Universitetssykehus

Acquisition of Vimentin by trogocytosis inhibits the NK cell-mediated immune response against circulating tumour cells (CTCs).
Interaction of CD99 and its ligands regulates immunoregulatory pathways in NK cells.
SLC1A5 augmentation bypasses NK cell transduction barriers to deliver complex CAR payloads.
Mitochondrial dysfunction and autophagy activation underlie NK cell impairment induced by Cannabis.
EGFR-Targeting IgG1 Antibody Enhances NK Cell-Mediated Tumor Killing in KRAS-Mutant Pancreatic Cancer.
Latent cytomegalovirus disrupts innate NK cell responses to P. falciparum and impairs parasite control in first infection in adults.
Clocking immunity: circadian modulation of NK cells and emerging timing perspectives.
NKG2A and NKp30 expression in NK cells correlates with preserved white matter and cortical thickness and reduced negative symptoms in psychiatric disorders.
SLy1-deficiency results in functional impaired, exhausted and senescent NK cells.
Advancing engineered nanoparticles for enhanced efficacy in cancer immunotherapy: optimizing nanoparticles for cancer immunotherapy.
Dual blockade of PD-1 and NKG2A prevents NK cell senescence and reprograms the immunosuppressive microenvironment in pancreatic cancer.
Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
IL-10 secretion by CD8 T cells orchestrates early NK cell recruitment and antitumor immunity after anti-VEGFR-2/PD-1 therapy.
Advancing CAR-NK cell therapy in solid tumors: Current landscape and future directions.
CRISPR-Cas9-mediated knock-in of cytomegalovirus US2 provides an alternative strategy for generating hypoimmunogenic hiPSC lines.
Vimentin trogocytosis as a novel mechanism of NK cell exhaustion by circulating tumor cells.
Next-generation of mesothelin-targeted CAR-T cells secreting anti-PD-L1 scFv for potent immunotherapy against 3D patient-derived colorectal cancer organoids.
Harnessing the Power of IL-12: Revolutionizing Cancer Therapy with Combinatorial Strategies.
Advances in Interleukin-2 Engineering and Delivery Systems for Cancer Immunotherapy.
Chimeric switch scaffold protein augments CAR synapse formation and signaling networks.
NKG2D as a molecular link between epithelial stress and immune activation in Crohn's disease: therapeutic implications.
Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.
Horizontal mitochondrial transfer and the tug-of-war between cancer cells and immune cells.
Protocol for detecting cytosol-retained proopiomelanocortin by fractionation and co-immunoprecipitation assay.
Building bundles by the numbers.
Adaptive mechanochemical mechanisms of the nucleus during confined cell migration.
The Lysosome-Cathepsin Axis in Pancreatic Cancer: Mechanisms of Stromal Remodeling, Immune Evasion, and Therapy Resistance.
Planar cell polarity-directed cell crawling drives polarized epithelial morphogenesis.
ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.
Mechanisms and functions of intercellular mitochondria transfer to and from macrophages.
Hydrostatic pressure reduces the mechanosensitivity of cell migration.

Cell Mol Immunol. 2026 Jun 22.

Acquisition of Vimentin by trogocytosis inhibits the NK cell-mediated immune response against circulating tumour cells (CTCs).

Lu Zhao, Ran Li, Xiao-Yan Meng, Yu-Xiang Guo, Liu Liu, Si-Yi Li, Zhonglong Liu, Long-Wei Hu, Hai-Long Ma, Chao-Ji Shi, Qin Xu, Yue He.

  Natural killer (NK) cells frequently exhibit an exhausted state, which facilitates immune escape of circulating tumor cells (CTCs). However, the underlying mechanisms of NK cell dysfunction remain elusive. In this study, we identified a novel immune evasion mechanism whereby tumor cells deliver Vimentin to NK cells via NKp46-dependent trogocytosis, thereby impairing NK cell cytotoxicity. We observed the expression of nonendogenous proteins in NK cells isolated from CTCs from oral cancer patients but not in those from nondetectable patients. High-throughput proteomic analysis, flow cytometry, and confocal microscopy revealed that vimentin, a protein that is not endogenously expressed in NK cells, was significantly enriched in NK cells via NKp46-dependent trogocytosis. The tail domain of trogocytosed vimentin competed with CDC42 for binding to ARHGEF7 and inhibited its exchange activity. This disruption impaired CDC42-mediated actin polymerization, thus suppressing NK cell cytotoxicity. By delivering vimentin to NK cells, CTCs can suppress and evade attacks from NK cells. Crucially, pharmacological inhibition of vimentin trogocytosis increased the efficacy of NK cells in clearing CTCs in vivo and that of NK cell-based adoptive immunotherapies. Clinically, the frequency of vimentin (+) NK cells is correlated with the CTC burden and tumor recurrence in cancer patients. Our study reveals that trogocytosis acts as a conduit for the tumor-induced exhaustion of NK cells and proposes targeting Vimentin transfer as a therapeutic strategy to counteract tumor recurrence.

Keywords:  Circulating tumor cells; Immune evasion; NK cells; Trogocytosis

DOI:  https://doi.org/10.1038/s41423-026-01432-9
Front Immunol. 2026 ;17 1840402

Interaction of CD99 and its ligands regulates immunoregulatory pathways in NK cells.

Myint Myat Thu, Nuchjira Takheaw, Witida Laopajon, Watchara Kasinrerk, Supansa Pata.

  Natural killer (NK) cells play a key role in immune defense against tumors and viral infections through a balance of activating and inhibitory receptors. CD99 is a transmembrane glycoprotein involved in many biological processes; however, its role in NK cell receptor modulation remains incompletely understood. In this study, we investigated the effect of CD99 engagement on NK cells using a recombinant CD99 fusion protein upon stimulation with cytokine, interleukin (IL)-2. Peripheral blood mononuclear cells (PBMCs) and purified NK cells were analyzed to evaluate changes in several receptor expressions. Flow cytometric analysis demonstrated that the interaction between CD99 and its ligands modulates NK cell phenotypes, particularly through downregulation of natural cytotoxicity receptors (NCRs). Differential effects were observed between PBMCs and purified NK cell cultures, indicating the surrounding immune cell environment influences CD99-mediated immunomodulatory responses. Despite receptor modulation, no significant changes in cytokine production were observed in NK cells. These findings suggest that CD99 and its ligand interactions contribute to the regulation of NK cell activation states and receptor dynamics under activated conditions in a context-dependent manner.

Keywords:  CD99HIgG; activating receptors; co-stimulatory receptors; natural cytotoxicity receptors (NCRs); natural killer (NK) cells

DOI:  https://doi.org/10.3389/fimmu.2026.1840402
J Immunol. 2026 Jun 07. pii: vkag133. [Epub ahead of print]215(6):

SLC1A5 augmentation bypasses NK cell transduction barriers to deliver complex CAR payloads.

Soumyajit Das, Khanh Ha Nguyen, Tyler Fritsch, Shambhavi Borde, Els Verhoeyen, Sandro Matosevic.

  Reproducible and efficient genetic engineering of human NK cells remains a primary challenge to next-generation chimeric antigen receptor (CAR) therapies, specifically for larger constructs with multiple plasmids and transgenes. Lentiviral vectors (LVs) pseudotyped with baboon envelope (BaEV) outperform vesicular stomatitis virus G protein in transducing hematopoietic stem cells, T cells, B cells, and NK cells, but suffer from fusogenic toxicity in producer cells and lower virion yields (BaEV-TR). Here, we engineer an integrated viral receptor platform that overcomes these constraints and enables transduction of freshly isolated, resting NK cells. First, we generated a Sleeping Beauty-engineered HEK293T packaging cell line stably expressing the nonfusogenic BaEV-TR glycoprotein, enabling consistent and scalable production of high titer BaEV-TR-pseudotyped LVs. Using this system, we generated LVs encoding SLC1A5 and a large (∼9.6 kb) multifunctional CD73-GD2-NKG2D CAR (mCAR). Second, we augmented SLC1A5 expression in freshly-isolated human NK cells using PDK1 inhibitor BX-795 and BaEV-TR-pseudotyped LVs. Rapid SLC1A5 overexpression in NK cells enabled transduction of resting cells without prior expansion and significantly increased NK cell susceptibility to mCAR delivery, achieving robust expression of the complex CAR cassette and preserving NK cell phenotype, cytokine production, degranulation, proliferation, and cytotoxicity against aggressive solid tumor cell targets. This combined approach directly addresses major bottlenecks in CAR-NK cell manufacturing, providing a modular platform for programming NK cells with challenging and large payloads.

Keywords:  CAR-NK; SLC1A5; baboon-pseudotyped lentivirus; natural killer cells

DOI:  https://doi.org/10.1093/jimmun/vkag133
PLoS One. 2026 ;21(6): e0350750

Mitochondrial dysfunction and autophagy activation underlie NK cell impairment induced by Cannabis.

Andrée-Ann Bolduc, Tony Tremblay, Mikhlid H Almutairi, Abdelhabib Semlali, Lionel Loubaki.

Cannabis use continues to rise in Canada, prompting concerns due to its potential impact on immune function. This study investigated the effect of a cannabis joint extract (CJE) on natural killer (NK) cells and explored the mechanisms underlying its potential anti-inflammatory properties. Peripheral blood mononuclear cells (PBMCs) were exposed to varying concentrations of CJE to assess cytotoxicity. Flow cytometry was employed to evaluate oxidative stress, autophagy, mitochondrial membrane potential, caspase-3 activation, and DNA damage. Additionally, NK cell cytotoxicity, migration, and adhesion were analyzed. Data indicated that CJE exposure led to dose-dependent cytotoxicity in NK cells, primarily through apoptosis. Specifically, at a concentration of 3 μg/mL, CJE significantly increased reactive oxygen species (ROS), autophagy markers, caspase activation, and DNA damage, while reducing mitochondrial membrane potential. Moreover, CJE impaired NK cell-mediated killing of HeLa cells, though their migratory and adhesive abilities were unaffected. These findings evidence that cannabis can detrimentally affect NK cell viability and function via mechanisms involving autophagy and caspase-dependent apoptosis.

DOI: https://doi.org/10.1371/journal.pone.0350750
MedComm (2020). 2026 Jul;7(7): e70860

EGFR-Targeting IgG1 Antibody Enhances NK Cell-Mediated Tumor Killing in KRAS-Mutant Pancreatic Cancer.

Ruoxi Xiao, Xiaoxiao Li, Ping Li, Junjin Wang, Xiaoyuan Sun, Chenyang Zhao, Zimin Liu, Ruining Gong, Minghan Ren, Ke Lei, He Ren.

  KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) exhibits intrinsic resistance to epidermal growth factor receptor (EGFR)-targeted therapies owing to constitutive downstream pathway activation. Nevertheless, IgG1 antibodies may retain therapeutic activity through natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), thereby bypassing EGFR downstream signaling. However, whether EGFR-targeted IgG1 antibody-mediated ADCC remains effective in KRAS-mutant PDAC, and what determines therapeutic responsiveness, remain unclear. Here, we investigated whether nimotuzumab-mediated ADCC remains effective despite oncogenic KRAS signaling and explored the determinants of its therapeutic efficacy. Using complementary in vitro and in vivo models, including PDAC cell-NK cell co-culture systems, 3D tumor spheroids, and immunodeficient mouse models (subcutaneous and circulating tumor cell-derived xenografts), we demonstrated that combined nimotuzumab and adoptive NK cell therapy exerts potent antitumor efficacy in PDAC. Mechanistically, this treatment drives robust NK cell functional activation (CD107a/IFN-γ/TNF-α), enhances tumor homing, and induces immunogenic cell death. Collectively, our findings demonstrate that KRAS mutations do not compromise nimotuzumab-mediated ADCC, whereas tumor EGFR expression serves as a predictor of therapeutic responsiveness. Ultimately, this study establishes EGFR-directed NK cell immunotherapy as a promising therapeutic strategy for KRAS-mutant PDAC and provides a rationale for integrating targeted antibodies with cellular immunotherapies in other EGFR-expressing malignancies.

Keywords:  EGFR; NK cells; antibody‐dependent cellular cytotoxicity; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1002/mco2.70860
PLoS Pathog. 2026 Jun;22(6): e1014372

Latent cytomegalovirus disrupts innate NK cell responses to P. falciparum and impairs parasite control in first infection in adults.

Reena Mukhiya, Jessica R Loughland, Nicholas L Dooley, Zuleima Pava, Damian A Oyong, Dean W Andrew, Julianne Hamelink, Kiana Berry, James S McCarthy, Bridget E Barber, J Alejandro Lopez, Christian R Engwerda, Michelle J Boyle.

NK cells are innate and adaptive responders to malaria, with functional responses underpinned by NK cell heterogeneity. One driver of NK cell heterogeneity is latent CMV infection. Latent CMV infection negatively impacts adaptive immunity to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. We investigated the impact of latent CMV infection on innate NK cell responses to the malaria parasite in vitro in malaria naïve adults, and in vivo NK cell responses during a first controlled human malaria infection. We found that transcriptional activation of NK cells by parasites was attenuated in CMV seropositive individuals. Further, during a first malaria infection, markers of NK cell activation and cytotoxicity were reduced. This attenuated response was not restricted to a single NK phenotype but occurred across diverse NK cell phenotypes. Consistent with a global NK cell attenuation, IL12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cell perforin expression was associated with parasite control in CMV seronegative individuals during first malaria infection. Data highlight the interplay between pathogens and the host-immune response that influence clinical outcomes.

DOI: https://doi.org/10.1371/journal.ppat.1014372
Front Immunol. 2026 ;17 1739723

Clocking immunity: circadian modulation of NK cells and emerging timing perspectives.

Kun Liu, Xuanying Lv, Wen Wen.

  Natural killer (NK) cells show day-night variation in both number and effector function. We compile findings from human cohorts, animal models, and cell studies on how circadian timing shapes NK biology. Evidence spans daily changes in counts and readouts such as degranulation and IFN-γ; links to core clock modules (PER1/2, NFIL3/E4BP4, STRA13); and neuroendocrine inputs (sympathetic tone, glucocorticoids, melatonin). Acute sleep loss can transiently raise NK activity, whereas multi-day sleep deprivation or circadian misalignment lowers counts or function. Shift work studies and laboratory night-shift simulations show reductions in NK activity and phase-sensitive changes in transcriptional programs (e.g., AP-1/STAT), with effects amplified by irregular schedules and accumulated fatigue. Across cancer, depression, vitiligo, and infection, alterations are heterogeneous, often presenting as peak shifts or amplitude flattening rather than loss of rhythmicity. Photoperiod, season, age, and sex can modify these patterns. Current data support a circadian influence on NK biology, but the direction and magnitude of reported effects vary across species, sampling schedules, circadian phase definitions, tissue compartments, and NK-cell readouts. This heterogeneity underscores the need for longitudinal, high-frequency sampling with complementary continuous monitoring to define phase, amplitude, and stability across physiological and clinical contexts.

Keywords:  chronotherapy; circadian rhythms; degranulation; glucocorticoids; natural killer cells; neuroendocrine regulation; shift work; sleep deprivation

DOI:  https://doi.org/10.3389/fimmu.2026.1739723
J Affect Disord. 2026 Jun 26. pii: S0165-0327(26)01030-X. [Epub ahead of print] 122178

NKG2A and NKp30 expression in NK cells correlates with preserved white matter and cortical thickness and reduced negative symptoms in psychiatric disorders.

Alberto Inuggi, Tiziana Altosole, Andrea Escelsior, Laura Damele, Elisa Cilia, Luca Favilla, Giacomo Marenco, Bruno Sterlini, Chiara Uras, Barbara Parisi, Riccardo Guglielmo, Beatriz Pereira, Fabrizio Loiacono, Daniela Fenoglio, Gilberto Filaci, Mario Amore, Gianluca Serafini, Emanuela Marcenaro.

   BACKGROUND AND HYPOTHESIS: Immune dysregulation contributes to the pathophysiology of schizophrenia (SZ) and bipolar disorder (BD), but specific immune alterations remain unclear. Natural killer (NK) cells, regulated by a balance of activating and inhibitory receptors, are increasingly implicated in neuroimmune interactions. We hypothesized that distinct NK cell receptor expression patterns may identify patient subgroups characterized by preserved brain structure and reduced symptom burden.
STUDY DESIGN: We conducted deep immunophenotyping and unsupervised clustering of NK cells from 53 patients (32 BD, 21 SZ) and 25 healthy controls (HC). Frequencies of NK subsets defined by main receptor expression were examined. A subset of 58 participants also underwent MRI to assess cortical thickness and white matter microstructure. Associations between immune profiles, imaging measures and clinical symptoms were tested.
STUDY RESULTS: Across clustering models, we consistently identified a patient-specific cluster (PSI) characterized by increased NKG2A+NKp30+ NK cells and reduced double-negative (NKG2A-NKp30-) NK cells. This pattern was independent of classical CD56-based maturation. Patients in the PSI cluster showed preserved cortical thickness and white matter integrity compared with patients outside the cluster, who exhibited widespread reductions relative to HC controls. Furthermore, reduced double-negative NK frequencies correlated with lower burden of negative symptoms.
CONCLUSIONS: Co-expression of NKp30 and NKG2A defines a meaningful NK cell phenotype associated with immune regulation, preserved brain structure, and improved clinical outcomes in SZ and BD. This profile may represent a marker of immune resilience and neuroimmune homeostasis, with potential implications for early diagnosis, patient stratification, and novel therapeutic strategies.

Keywords:  Bipolar disorder; Cortical thickness; Natural killer cells; Negative symptoms; Skizzophrenia; White matter

DOI:  https://doi.org/10.1016/j.jad.2026.122178
Front Immunol. 2026 ;17 1836862

SLy1-deficiency results in functional impaired, exhausted and senescent NK cells.

Lisa Rebmann, Victoria Schwenck, Carolin Blumendeller, Isabelle Grund, Jannika Botzenhardt, Sandra Beer-Hammer.

   Introduction: SLy1 is an emerging adapter protein, exclusively expressed in lymphocytes. In NK cells it serves as ribosomal stabilizer and plays an important role for their maturation, survival and functionality. SLy1-deficient (SLy1KO) NK cells exhibit ribosomal instability, which leads to excessive amounts of free ribosomal proteins followed by an accumulation of p53. However, the characterization of the impairment and the dependence on p53 has not yet been elucidated.
Objective: This study aimed to analyze phenotypical and functional characteristics of SLy1- and p53-deficient NK cells and to understand which impairments depend on both proteins.
Results: We established a SLy1WT/KO; p53WT/KO mouse strain and were able to reveal that the reported reduction in viability, cytotoxicity and expression of activating surface receptors in SLy1KO NK cells is mediated by p53. Moreover, we observed that a SLy1KO also leads to decreased NK cell numbers and to increased levels of senescence and exhaustion, independently of p53. Further, we detected elevated protein and mRNA levels of the DNA damage response mediators, which could be responsible for the observed phenotypic alterations.
Conclusion: In brief, we demonstrated that SLy1 is indispensable for adequate numbers of viable, activatable NK cells with an intact cytolytic capacity, and that those phenotypic alterations are p53-mediated. Furthermore, the absence of SLy1 leads to senescence and exhaustion of NK cells in an p53-independant manner. These findings correlate with the recently shown association of human SLy1-mutations with specific types of common variable immunodeficiencies. We therefore strongly recommend testing for mutations in the gene locus, especially in patients with unclear immunodeficiencies.

Keywords:  NK cells; SLy1/SASH3; exhaustion; p53; ribosome; senescence

DOI:  https://doi.org/10.3389/fimmu.2026.1836862
Mol Biol Rep. 2026 Jun 24. pii: 1006. [Epub ahead of print]53(1):

Advancing engineered nanoparticles for enhanced efficacy in cancer immunotherapy: optimizing nanoparticles for cancer immunotherapy.

Mukta Basu, Elizabeth Mahapatra, Deepika Rai, Abhimanyu Thakur.

  Recent evidence on resistance to immune checkpoint inhibitors (ICIs) has necessitated the exploration of alternative cancer therapies with increased treatment responsiveness among patients, especially for solid tumors. Phototherapy with red or near-infrared light is considered as one such potential approach, but it espouses limited efficacy in treating solid tumors and aggravates cancer progression in some instances. In contrast, genetically engineered T cells bearing chimeric antigen receptors (CAR) targeting tumor-specific neo-antigens have demonstrated significant therapeutic potential and have advanced into clinical trials. Several reports have annotated numerous neo-antigens, eventually enhancing CAR T-cell design and efficacy. Nevertheless, numerous clinical trials envisaged 'hyperimmune response' as a limitation of effective CAR T treatment for cold tumors, driving the development of CAR engineered macrophages (CAR M) and natural killer (CAR NK) cells which efficiently infiltrated cold tumors and elicited better treatment response. CAR NK therapy is advantageous for its MHC independent cytotoxicity which prevents cytokine storm along with graft versus host disease (GVHD). However, isolation, gene manipulation and proliferation of the immune cells from patients is not time efficient. Involving nanotechnology has enhanced the time and CAR DNA delivery dependent efficacy of CAR therapy in all immune cells. Nanoparticles containing cationic polymers like polyethyleneimine (PEI), poly(L-lysine), and poly(2-dimethylamino) ethyl methacrylate effectively delivers DNA to the specific immune cells, thereby increasing the responsiveness towards the CAR therapy. In this review, we highlight promising avenues with potentials to improve clinical outcomes that have emerged from the convergence of nanotechnology and CAR based immunotherapy.

Keywords:  CAR; CAR M; CAR NK; CAR T; NIR-phototherapy; Nanoparticle

DOI:  https://doi.org/10.1007/s11033-026-12171-5
Cell Rep. 2026 Jun 20. pii: S2211-1247(26)00661-3. [Epub ahead of print]45(7): 117583

Dual blockade of PD-1 and NKG2A prevents NK cell senescence and reprograms the immunosuppressive microenvironment in pancreatic cancer.

Yu Zhang, Xueyan Zhou, Yuhao Wei, Hao Zhang, Yunuo Zhao, Huan Tong, Zedong Jiang, Guangqi Li, Yuting Jiang, Xiaomeng Yin, Shen Li, Nan Lin, Lusi Feng, Haorui Zhou, Qianlong Kang, Jieping Qiu, Jingwen Wei, Keqin Tan, Xiaoqian Yang, Renwei Li, Jiaqing Yang, Shiyi Tang, Shengxin Zhang, Jifeng Liu, Xuelei Ma.

  Immune checkpoint blockade (ICB) shows limited efficacy in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrate that ICB-induced IFN-γ signaling upregulates H2-T23 on pancreatic tumor cells, which interacts with NKG2A on NK cells to induce NK cell senescence through activation of p38 MAPK and STAT1/3 pathways. This impairs NK cell cytotoxicity and restricts antitumor immunity. Dual blockade of PD-1 and NKG2A effectively prevents NK cell senescence, restores NK cell function, and enhances antitumor immunity. Mechanistically, the combination therapy promotes NK cell-derived CCL5 and facilitates CD8+ T cell recruitment in an NK cell-dependent manner, thereby activating both innate and adaptive immunity. Analysis of single-cell sequencing data across nine cancer types further revealed increased NK cell senescence after immunotherapy, suggesting a potentially common pan-cancer mechanism. These findings identify NK cell senescence as a key mechanism underlying immunotherapy resistance and support dual targeting of PD-1 and NKG2A as a promising therapeutic strategy for PDAC.

Keywords:  CP: cancer; CP: immunology; Parabrachial nucleus; chemogenetics; chronic pain; optogenetics

DOI:  https://doi.org/10.1016/j.celrep.2026.117583
Nature. 2026 Jul;655(8121): 45-46

Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.

Amaia Zabala-Letona, Arkaitz Carracedo.



Keywords:  Biochemistry; Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-026-01802-3
J Immunother Cancer. 2026 Jun 22. pii: e015243. [Epub ahead of print]14(6):

IL-10 secretion by CD8 T cells orchestrates early NK cell recruitment and antitumor immunity after anti-VEGFR-2/PD-1 therapy.

Mannon Geindreau, Cassandre Pignol, Loïs Coënon, Alexis Varin, Cindy Racoeur, Lylou Milian, Nolwenn Roger, Fanny Chalmin, Thibault Vernet, Line Alibert, Pierre-Simon Bellaye, Marion Thibaudin, Cynthia Louis, Ian Wicks, Caroline Truntzer, Romain Boidot, Catherine Paul, Baptiste Lamarthée, Frederique Vegran, Francois Ghiringhelli, Mélanie Bruchard.

   BACKGROUND: The combination of antiangiogenic therapy with immune checkpoint blockade has demonstrated significant clinical benefits in various cancers, however, the precise mechanisms of action on the immune system are not fully understood. In particular, the early intratumoral immune responses induced by angiogenesis inhibition remain unclear.
METHODS: Using preclinical models of colorectal cancer, we examined the immune changes elicited by combined vascular endothelial growth factor receptor-2 (VEGFR-2) and programmed cell death protein-1 (PD-1) blockade.
RESULTS: Our findings reveal that CD8 T cells respond directly and early to VEGFR-2 inhibition, preceding the acquisition of overt cytotoxic function. Shortly after treatment, intratumoral CD8 T cells expanded and produced interleukin-10 (IL-10). Unexpectedly, this CD8 T cell-derived IL-10 promoted the recruitment of natural killer (NK) cells into tumors. Recruited NK cells subsequently gained effector activity and produced granulocyte-macrophage colony-stimulating factor, which supported macrophage maturation and the induction of CXCL11. This sequence of events enhanced secondary CD8 T-cell infiltration and sustained antitumor immune activity. Disruption of IL-10 signaling or NK-cell function eliminated the therapeutic benefit of combined VEGFR-2 and PD-1 blockade, whereas regulatory T-cell depletion further improved tumor control.
CONCLUSIONS: Together, these findings identify an unanticipated role for CD8 T cell-derived IL-10 in coordinating early innate and adaptive immune responses following angiogenesis inhibition and define an immune program initiated by VEGFR-2 blockade that is required for therapeutic efficacy in two preclinical colorectal cancer models.

Keywords:  Adaptive; Colorectal Cancer; Combination therapy; Immune Checkpoint Inhibitor; Natural killer - NK

DOI:  https://doi.org/10.1136/jitc-2026-015243
Cell Rep Med. 2026 Jun 25. pii: S2666-3791(26)00298-3. [Epub ahead of print] 102881

Advancing CAR-NK cell therapy in solid tumors: Current landscape and future directions.

Gohar Shahwar Manzar, Md Faqrul Hasan, Madison Moore, Silvia Tiberti, Nahum Puebla Osorio, Rafet Basar, May Daher.

  Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have emerged as a promising modern immunotherapeutic strategy, offering advantages over CAR-T cell therapy due to their innate cytotoxicity, safety profile, and potential for scalable, off-the-shelf allogeneic manufacturing. CAR-NK cells can be generated from multiple sources, with recent clinical studies demonstrating notable efficacy and lack of severe toxicity in hematologic malignancies. Nevertheless, the translation of this success to solid tumors is hampered by limited NK cell persistence, trafficking and infiltration challenges, and the hostile, immunosuppressive tumor microenvironment. This review provides a comprehensive synthesis of recent advances and innovations in CAR-NK cell engineering, addresses challenges posed by the solid tumor microenvironment, and highlights both rational preclinical strategies and early-phase clinical trials in solid tumors, underscoring the evolving and transformative promise of CAR-NK therapy for a broader range of human cancers in the near future.

Keywords:  CAR-NK; cellular immunotherapy; chimeric antigen receptor; solid tumors

DOI:  https://doi.org/10.1016/j.xcrm.2026.102881
Sci Rep. 2026 Jun 23.

CRISPR-Cas9-mediated knock-in of cytomegalovirus US2 provides an alternative strategy for generating hypoimmunogenic hiPSC lines.

Juan J Novoa, Lonneke H Gaykema, Juliette A de Klerk, Janneke H D Peerlings, Rianne Y van Nieuwland, Arno van der Slik, Francijna E van den Hil, Valeria V Orlova, Manuel A F V Gonçalves, Cathelijne W van den Berg, Ton J Rabelink, Arnaud Zaldumbide.

Mismatches in HLA haplotypes between donors and recipients significantly increase the risk of graft failure due to immune rejection. Knockout (KO) of beta-2 microglobulin (B2M) is the current standard for eliminating HLA class I (HLA-I) surface expression and protecting allogeneic products from T-cell-mediated rejection; however, complete HLA-I ablation can trigger natural killer (NK) cell "missing-self" responses and disrupt critical immune-regulatory interactions. To address these limitations, we introduced a cytomegalovirus-derived US2 encoding sequence into the AAVS1 safe-harbor locus of a human induced pluripotent stem cell (hiPSC) line. Flow cytometry showed that US2 selectively abrogates HLA-A2 surface expression while retaining low levels of total HLA-I. In coculture assays, US2 expression abolished HLA-A2 alloreactive T-cell activation without increasing NK cell degranulation, indicating preserved inhibitory signaling. Together, these findings establish US2-mediated immune evasion as a refined single-edit alternative to B2M KO, enabling selective HLA-I modulation while preserving critical immune-regulatory interactions.

DOI: https://doi.org/10.1038/s41598-026-58651-3
Cell Mol Immunol. 2026 Jun 24.

Vimentin trogocytosis as a novel mechanism of NK cell exhaustion by circulating tumor cells.

Hyo-Jeong Cha, Changwan Hong.

DOI: https://doi.org/10.1038/s41423-026-01443-6
BMC Med. 2026 Jun 26.

Next-generation of mesothelin-targeted CAR-T cells secreting anti-PD-L1 scFv for potent immunotherapy against 3D patient-derived colorectal cancer organoids.

Nattaporn Phanthaphol, Pattara Kanoksing, Woramin Riansuwan, Siriluck Prapasrivorakul, Pornraksa Ovartchaiyapong, Aitsariya Mongkhonsupphawan, Surat Phumphuang, Mutita Junking, Peti Thuwajit, Pa-Thai Yenchitsomanus, Chanitra Thuwajit, Suyanee Thongchot.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have revolutionized the landscape of cancer treatment, particularly in hematological malignancies. However, their successful translation to solid tumors remains limited by several barriers, including immunosuppressive tumor microenvironment and on-target/off-tumor toxicity. One promising strategy to enhance efficacy of CAR-T cells is the rational selection of tumor-specific antigens coupled with engineering strategies that incorporate localized immune modulation, such as CAR-T cells secreting immune checkpoint-blocking anti-PD-L1 scFv.
METHODS: To better model therapeutic responses, we established a dynamic real-time autologous co-culture platform integrating colorectal cancer (CRC) patient-derived organoids (PDOs) and CAR-T cells to assess infiltration, persistence, and cytotoxicity ex vivo. Although early clinical trials of mesothelin (MSLN)-directed CAR-T cells have demonstrated high safety, their anti-tumor efficacy remains modest, highlighting the need for improved constructs. Therefore, we engineered anti-MSLN-CAR4-T cells using fully human anti-MSLN scFv linked to a triple costimulatory backbone (CD28, 4-1BB, and CD27) fused to CD3ζ, and anti-MSLN-CAR5-T cells, incorporating an additional anti-PD-L1 scFv.
RESULTS: Both CAR4- and CAR5-T cells exhibited comparable cytotoxic efficacy against MSLNHigh/PD-L1High autologous PDOs. However, only anti-MSLN-CAR5-T cells were able to sustain potent killing activity against PD-L1High PDOs with high IFN-γ/cytolytic cytokine production at a low effector-to-target ratio (5:1), reflecting improved resilience to PD-L1-mediated suppression.
CONCLUSIONS: Finally, our 14-day ex vivo CRC-PDOs/CAR-T platform provides a promising rapid and translational tool for tumor-associated antigen validation, streamlined PDO isolation, autologous CAR-T cytotoxicity testing, and personalized immunotherapy optimization in solid tumors.

Keywords:  CAR-T cells; Colorectal cancer; MSLN; PD-L1; Patient-derived organoids

DOI:  https://doi.org/10.1186/s12916-026-05004-6
Cytokine. 2026 Jun 23. pii: S1043-4666(26)00075-X. [Epub ahead of print]205 157180

Harnessing the Power of IL-12: Revolutionizing Cancer Therapy with Combinatorial Strategies.

Yuxi Zhang, Jing Tian, Wen Cheng, Xiangdong Gao, Jun Yin.

  Interleukin-12 (IL-12) is a potent immunostimulatory cytokine that enhances T cell and natural killer (NK) cell activation and promotes Th1-type immune responses. However, its clinical application as monotherapy has been hampered by systemic toxicity and limited efficacy. As a result, IL-12-based combination strategies have attracted increasing attention in cancer therapy. This review summarizes the immune regulatory mechanisms by which IL-12 remodels the tumor microenvironment and enhances antitumor immunity. We discuss recent preclinical and clinical advances in combining IL-12 with immune checkpoint inhibitors, chemotherapy, cellular therapies such as CAR-T cells, and cancer vaccines. In addition, emerging synergistic approaches involving targeted therapies and STING agonists are highlighted. Finally, we address current challenges and future directions, focusing on strategies to improve tumor specificity and minimize systemic toxicity. Overall, this review emphasizes IL-12 as a key immunomodulatory component in next-generation combination cancer therapies.

Keywords:  CAR-T cells; Chemotherapy; Combination therapy; Immune checkpoint inhibitor; Immune modulation; Interleukin-12

DOI:  https://doi.org/10.1016/j.cyto.2026.157180
ACS Appl Bio Mater. 2026 Jun 24.

Advances in Interleukin-2 Engineering and Delivery Systems for Cancer Immunotherapy.

Xiaolei Du, Yujie Chen, Mengchen Xu, Hongyun Liu, Jiafei Liu, Feihe Ma, Linqi Shi.

  Interleukin-2 (IL-2) is a multifunctional cytokine that plays a central role in the proliferation, differentiation, and function of regulatory T cells (Tregs), effector T cells, and natural killer (NK) cells. Given the immunomodulatory properties of IL-2, high-dose IL-2 has been approved for the treatment of metastatic renal cell carcinoma and melanoma, making it the first cytokine-based immunotherapy to achieve clinical translation. However, the extremely short half-life in vivo, significant systemic toxicity, and immune suppression mediated by the preferential activation of Tregs severely limit its clinical application and therapeutic efficacy. In recent years, with a deeper understanding of the composition and distribution of IL-2 receptor subunits and their downstream signaling pathways, protein engineering research aimed at improving the therapeutic index of IL-2 has become increasingly active. This article reviews the structural-functional relationships of IL-2 and its receptor complexes, summarizes engineering strategies for IL-2 variants, and examines IL-2 delivery systems designed to achieve selective targeting of effector cells in cancer immunotherapy. These approaches have made progress in mitigating IL-2-induced systemic toxicity, providing a design basis for the development of safer and more effective IL-2 therapies.

Keywords:  cancer therapy; drug delivery systems; engineering modification; immune mechanisms; interleukin-2

DOI:  https://doi.org/10.1021/acsabm.6c00836
J Immunother Cancer. 2026 Jun 25. pii: e014970. [Epub ahead of print]14(6):

Chimeric switch scaffold protein augments CAR synapse formation and signaling networks.

Cho I Park, Segi Kim, Hwanyong Shim, Minh Ha Nguyen, Won-Ki Cho, Chan Hyuk Kim.

   BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has achieved clinical success in hematologic malignancies, but remains limited in solid tumors due to immune checkpoint-mediated suppression and intrinsic signaling constraints. Unlike T-cell receptors (TCRs), CARs fail to efficiently recruit the linker for activation of T cells (LAT) signalosome, resulting in suboptimal signal propagation and unstable immunological synapse organization.
METHODS: To address this limitation, we engineered a programmed cell death protein 1 (PD-1)-LAT (PLAT) chimeric switch scaffold that couples PD-1 engagement to LAT-dependent proximal signaling. We compared the signaling kinetics, synaptic architecture, and antitumor efficacy of PLAT-expressing HER2 CAR T cells against those expressing conventional PD-1-CD28 switch receptors or dominant-negative PD-1 using biochemical signaling assays, quantitative imaging analysis, chronic antigen stimulation models, and in vivo xenograft validation.
RESULTS: PLAT enhanced LAT phosphorylation and nucleated LAT-associated signaling complexes on programmed death-ligand 1 engagement. This reorganized the CAR immune synapse into a concentric, TCR-like architecture, restoring proximal signaling strength. This signaling reprogramming resulted in increased calcium flux and NFAT/NF-κB activation, driving enhanced cytotoxicity, sustained proliferation, and resistance to functional exhaustion under chronic antigen exposure. In direct comparisons, PLAT outperformed conventional PD-1-CD28 switch receptors in early functional responses and demonstrated superior functional durability and antitumor activity in vivo compared with dominant-negative PD-1 strategies.
CONCLUSIONS: These findings establish PLAT as a scaffold-based strategy that directly addresses intrinsic CAR signaling deficiencies by converting immune checkpoint engagement into LAT-dependent proximal signaling restoration. This work provides a new framework for engineering CAR T cells with improved function and persistence in immunosuppressive tumor environments.

Keywords:  Chimeric antigen receptor - CAR; Immunosuppression; Immunotherapy; T cell Receptor - TCR

DOI:  https://doi.org/10.1136/jitc-2026-014970
Cell Mol Biol (Noisy-le-grand). 2026 Mar 31. 72(3): 63-67

NKG2D as a molecular link between epithelial stress and immune activation in Crohn's disease: therapeutic implications.

Alexander V Blagov, Marina D Sazonova, Anastasia I Ryzhkova, Mikhail A Popov, Alexandra V Mishina, Arkady A Metelkin, Alexander N Orekhov, Igor A Tarakanov, Vasily P Karagodin, Margarita A Sazonova, Yuri V Arkhipenko.

Crohn's disease (CD) is a chronic inflammatory bowel disorder driven by dysregulated immune responses, epithelial barrier dysfunction, and progressive tissue damage. Despite advances in biologic therapies, treatment resistance and loss of response remain common. The activating receptor NKG2D, expressed on natural killer cells and T cell subsets, recognizes stress-induced ligands (MICA, MICB, ULBP) upregulated on intestinal epithelial cells under inflammatory conditions. In CD, sustained ligand expression promotes NKG2D-dependent cytotoxicity, pro-inflammatory cytokine release (IFN-γ, IL-17), and lymphocyte trafficking into the mucosa, perpetuating a cycle of epithelial injury and chronic inflammation. Preclinical colitis models and clinical trials with anti-NKG2D monoclonal antibodies (e.g., NNC0142-0002) demonstrate reduced disease activity, improved histological outcomes, and induction of remission in moderate-to-severe CD patients. However, challenges remain, including potential impairment of immune surveillance against infections and tumors, patient heterogeneity, and pathway redundancy. Future directions include biomarker-guided patient selection, combination therapies with anti-TNF or anti-integrin agents, and next-generation biologics such as bispecific antibodies. Understanding the cellular and molecular basis of NKG2D signaling in mucosal inflammation positions this receptor as a promising, mechanistically anchored therapeutic target in Crohn's disease.

DOI: https://doi.org/10.14715/cmb/2025.72.3.8
Sci Signal. 2026 Jun 23. 19(943): eadw1017

Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.

Ana Fernández-Barrecheguren, Adrián Fernández-Rego, Lucía Fuentes-Cantos, Tirso Pons, Belén S Estrada, Marta Iborra-Pernichi, María Velasco de la Esperanza, Tahmineh Ebrahimi, Ana Sagrega-Aparisi, Sara Cogliati, Nuria Martínez-Martín, Rodrigo Jiménez-Saiz, Yolanda R Carrasco.

To mount a robust T cell-dependent immune response, antigen-specific B lymphocytes require the stimulation of the transmembrane receptor CD40 through immune synapse formation with CD4+ T follicular helper cells. CD40 stimulates the activation of mammalian target of rapamycin complex 1 (mTORC1) and remodels mitochondria to meet the increased bioenergetic and anabolic demands of activated B cells. Here, we found that diacylglycerol kinase ζ (DGKζ) supported mTORC1 activation downstream of CD40 stimulation in mouse B cells. We showed that DGKζ was required for organellar translocation to the CD40-mediated immune synapse and for the recruitment of mTORC1 to lysosomes, the latter of which was necessary for mTORC1 activation and function. The production of phosphatidic acid by DGKζ was crucial for these processes. DGKζ-/- B cells exhibited defects in protein biosynthesis, metabolite transporter expression, and cell cycle progression, together with dysregulation of the transcriptional network that determines B cell fate. To sustain their bioenergetic and metabolic demands, DGKζ-/- B cells enhanced their mitochondrial function. Together, these effects of DGKζ loss led to decreases in germinal center responses and in the generation of long-lived plasma cells and memory B cells in mice. Thus, our data identify DGKζ as an essential mediator of CD40 functions in the B cell immune response.

DOI: https://doi.org/10.1126/scisignal.adw1017
Trends Cancer. 2026 Jun 20. pii: S2405-8033(26)00126-3. [Epub ahead of print]

Horizontal mitochondrial transfer and the tug-of-war between cancer cells and immune cells.

Jaromir Novak, Denisa Hortova, Berwini Endaya, Magdalena Krulova, Michael V Berridge, Jiri Neuzil.

  Horizontal mitochondrial transfer (HMT) is an emerging field of cell biology. Since its discovery, HMT has been extensively studied in the context of cancer due to the essential role of mitochondria in fueling the proliferation of tumor cells. The role of HMT in cancer, however, reaches far beyond a simple mechanism of organelle acquisition. Indeed, several recent studies have demonstrated HMT from cancer to immune cells and vice versa, with a profound impact on antitumor immune responses and potentially on immunotherapy efficacy. In this opinion article, we propose that HMT should receive attention as another modulatable mechanism of the functional tug-of-war between cancer and immune cells, further contributing to the complexity of the tumor microenvironment and likely sculpting the outcome of competition between the two teams of cells.

Keywords:  horizontal mitochondrial transfer; immunotherapy; tumor-infiltrating lymphocytes; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.trecan.2026.05.008
STAR Protoc. 2026 Jun 24. pii: S2666-1667(26)00315-1. [Epub ahead of print]7(3): 104662

Protocol for detecting cytosol-retained proopiomelanocortin by fractionation and co-immunoprecipitation assay.

Sang-Hyeon Mun, Cheol-Sang Hwang.

  Signal peptide (SP)-uncleaved proopiomelanocortin (POMC) accumulates in the cytosol when ER translocation or protein quality control is perturbed. Here, we present a protocol to prepare and validate a POMC SP-specific antibody. We then use this antibody to detect cytosol-retained SP-uncleaved POMC in mammalian cells. We describe steps for using sequential digitonin-based semi-permeabilization followed by Triton X-100 lysis to isolate cytosolic and organelle fractions. We then detect cytosolic POMC by immunoblotting upon genetic depletion or enrich it by SP-specific immunoprecipitation. For complete details on the use and execution of this protocol, please refer to Mun et al.1.

Keywords:  Cell Biology; Molecular Biology; Protein Biochemistry

DOI:  https://doi.org/10.1016/j.xpro.2026.104662
Elife. 2026 Jun 23. pii: e111840. [Epub ahead of print]15

Building bundles by the numbers.

Christian Vanhille-Campos, Anđela Šarić.

  The size and shape of cytoskeletal bundles, essential regulators of cell function, emerge from collective filament assembly rather than precise size-control mechanisms.

Keywords:  actin bundles; actin filaments; cell protrusions; cytoskeleton; eukaryotic cells; none; physics of living systems

DOI:  https://doi.org/10.7554/eLife.111840
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2604716123

Adaptive mechanochemical mechanisms of the nucleus during confined cell migration.

Wenying Luo, Xindong Chen, Bo Li, Xi-Qiao Feng.

  Cell migration through spatially confined microenvironments occurs in many biological processes such as embryonic development, immune surveillance, and cancer metastasis. A major bottleneck during such migration is the nucleus, which acts not only as a rigid mechanical obstacle but also as a crucial mechanosensor that modulates downstream signaling pathways. However, it remains poorly understood how nuclear deformation and mechanosensation together regulate cell migration through confined spaces. Here, we propose a three-dimensional (3D) mechanochemical model of confined nuclear translocation that integrates nuclear deformation with deformation-induced calcium signaling and subsequent regulation of cytoskeletal contractility. We show that cells undergo adaptive nuclear deformation, including nuclear envelope elongation and 3D buckling, to efficiently navigate confinements of varying sizes. There exists a biphasic relation between nuclear velocity and confinement size, arising from the interplay between nuclear deformability and mechanosensitive feedback. We demonstrate that local nuclear envelope rupture can occur under large deformation, enabling nuclear translocation through extreme confinements, as observed in prior experiments. Furthermore, we elucidate the critical roles of chromatin organization in nuclear translocation. This work reveals key mechanochemical mechanisms driving confined cell migration and provides a theoretical framework for studying nuclear dynamics across physiological and pathological contexts.

Keywords:  confined cell migration; mechanochemical model; mechanotransduction; nuclear dynamics

DOI:  https://doi.org/10.1073/pnas.2604716123
Biomolecules. 2026 Jun 02. pii: 824. [Epub ahead of print]16(6):

The Lysosome-Cathepsin Axis in Pancreatic Cancer: Mechanisms of Stromal Remodeling, Immune Evasion, and Therapy Resistance.

Nika Mazej Jeram, Emanuela Senjor, Janko Kos, Milica Perišić Nanut.

  Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma accounting for the vast majority of cases and characterized by extensive desmoplasia, immune exclusion, and resistance to systemic therapies. Increasing evidence implicates lysosomal cathepsins as important regulators of these defining features of pancreatic tumor biology. Cathepsin-dependent proteolysis and lysosome-associated signaling pathways contribute to extracellular matrix remodeling, regulate immune cell trafficking, and influence antigen processing and presentation. Beyond their classical degradative functions, cathepsins participate in stress-adaptive cellular programs linked to autophagy, metabolic regulation, and proteostasis, supporting tumor cell survival under hypoxic, nutrient-limited, and therapy-induced stress conditions. Within the tumor microenvironment, dysregulated cathepsin activity promotes immune evasion by reshaping cytokine networks, impairing effective antigen presentation, and reinforcing physical and functional barriers to cytotoxic T-cell infiltration. Collectively, these mechanisms position the lysosome-cathepsin system as a central regulator of proteolytic remodeling, immune exclusion, and adaptive therapy resistance in pancreatic cancer, highlighting its potential relevance for emerging combinatorial therapeutic strategies.

Keywords:  antigen presentation; autophagy; cytotoxic cells; extracellular matrix remodeling; immune evasion; lysosomal cathepsins; pancreatic ductal adenocarcinoma; therapeutic resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/biom16060824
Curr Biol. 2026 Jun 23. pii: S0960-9822(26)00670-6. [Epub ahead of print]

Planar cell polarity-directed cell crawling drives polarized epithelial morphogenesis.

Rishabh Sharan, XinXin Du, Liliya Leybova, Anyoko Sewavi, Brooke K Phillips, Abhishek Biswas, Danelle Devenport.

  During epithelial morphogenesis, cell polarity aligns individual cell behaviors into collective motions that shape developing tissues. Here, we combine experiments with computational modeling to investigate how cell-scale forces oriented by planar cell polarity (PCP) direct the collective, counter-rotational cell flows that occur during hair placode morphogenesis. Unexpectedly, we find that junctional myosin and PCP protein localization are not co-correlated with junction shrinkage, indicating the role of PCP during placode polarization is not to direct apical neighbor exchanges. Instead, we find that PCP directs anterior-directed crawling of placode cells along the basal surface of the tissue through a mechanism that requires integrins and the cell-crawling regulator Rac1. Modeling the placode as a three-dimensional continuum viscoelastic fluid, we find that active forces from cell crawling at the basal surface are sufficient to generate the experimentally observed counter-rotational cell motion at the apical surface. Our results show an unexpected role for PCP in epithelial morphogenesis, centering the basal surface as the site of force generation.

Keywords:  PCP; basal; cell migration; collective migration; epithelial morphogenesis; hair follicle; hair placode; planar cell polarity; protrusions

DOI:  https://doi.org/10.1016/j.cub.2026.05.065
Nucleic Acids Res. 2026 Jun 22. pii: gkag641. [Epub ahead of print]54(12):

ATF4 and CHOP coordinate endoplasmic reticulum stress-responsive gene programs through enhancer activation and chromatin looping.

Jung-Sik Joo, Mikyoung Kim, Sugyung Kim, Hyejin Kim, Hyoung-Pyo Kim.

Endoplasmic reticulum (ER) stress triggers transcriptional programs that promote either adaptation or apoptosis, yet the epigenetic mechanisms underlying this response remain incompletely understood. Here, integrated multi-omics analyses of unfolded protein response transcription factor knockout cells identify ATF4 as a dominant regulator of ER stress-responsive enhancer activation and chromatin looping. Loss of ATF4 markedly impairs stress-induced H3K27ac accumulation and enhancer-promoter interactions at ATF4-associated regulatory elements, establishing ATF4 as a central organizer of the stress-responsive regulatory landscape. We further identify CHOP as a key functional partner of ATF4 during ER stress. Integrative analyses of ATF4 occupancy and H3K27ac landscapes in CHOP-knockout cells reveal that CHOP selectively modulates ATF4-dependent enhancer activity and controls distinct subsets of stress-responsive genes. This cooperation preferentially promotes apoptosis-associated transcriptional programs while having limited effects on core adaptive responses. Together, our findings define a hierarchical regulatory framework in which ATF4 establishes enhancer activation and chromatin looping networks, whereas CHOP selectively diversifies their output to specify ER stress-responsive gene programs.

DOI: https://doi.org/10.1093/nar/gkag641
J Immunol. 2026 Jun 07. pii: vkag147. [Epub ahead of print]215(6):

Mechanisms and functions of intercellular mitochondria transfer to and from macrophages.

Wentong Jia, Jonathan R Brestoff.

  Cell-to-cell communication is essential for maintaining homeostasis and coordinating complex biological processes in multicellular organisms. Classically, cells communicate using secreted peptides and metabolites and through cell contact-dependent signaling. Emerging studies over the past 20 years indicate that many cell types, including innate immune cells such as macrophages, participate in a process called intercellular mitochondria transfer, in which macrophages either donate their own mitochondria to other cells or accept mitochondria originating from another cell type. This raises the intriguing possibility that macrophages use mitochondria transfer as a mechanism of cell-to-cell communication. In this review, we describe the distinct mechanisms and functional roles of mitochondria transfer in macrophages across different organ systems and highlight how this biology contributes to health maintenance and disease pathogenesis.

Keywords:  acceptor; cell-to-cell communication; donor; intercellular mitochondria transfer; macrophage

DOI:  https://doi.org/10.1093/jimmun/vkag147
Sci Adv. 2026 Jun 26. 12(26): eaed0981

Hydrostatic pressure reduces the mechanosensitivity of cell migration.

Ayuba Akinpelu, Abby Weaver, Farnaz Hemmati, Ethan Coker, Farshad Amiri, Chrystalla Stylianou, Ravi S Vaghasiya, Matthew T Garnett, Daniel Nweze, Maria Kalli, Symone Alexander, Triantafyllos Stylianopoulos, Yizeng Li, Panagiotis Mistriotis.

Cells sense and respond to diverse physical cues as they migrate toward distant sites. While much is known about the roles of cellular molecules in the regulation of mechanosensitivity, our understanding of how extracellular cues influence this property remains limited. Here, we show that prolonged exposure to elevated, yet (patho)physiologically relevant, extracellular hydrostatic pressure decreases migration sensitivity to substrate stiffness, fluid viscosity, fluid forces, and hydraulic resistance. Reduced mechanosensitivity can persist for days after the high-pressure cue is removed, indicating that cells retain a memory of hydrostatic pressure. Mechanistically, high pressure down-regulates the Rho/MRTF/SRF pathway, activating a myosin II-independent mechanosensing mechanism that shifts the maximum cell speed toward stiffer substrates, as predicted mathematically and demonstrated experimentally. Stiffer substrates increase migration of preconditioned cells by strengthening focal adhesions and redistributing them to the cell periphery to support Arp2/3-dependent lamellipodia extension. Collectively, hydrostatic pressure reprograms the mechanosensing machinery to drive lasting effects on cell mechanosensitivity.

DOI: https://doi.org/10.1126/sciadv.aed0981