Cellular Immunology[JOURNAL]
Sun
200 papers
The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro.
Sirina J, D'Hooghe LE, Singhvi-Hanns LA … +4 more , Cole SL, Shock A, Holliday ND, Stoddart LA
Cell Immunol · 2026 Jun · PMID 42385333 · Publisher ↗
The neonatal Fc receptor (FcRn) recycles immunoglobulin G (IgG) in cells and is responsible for the long half-life of IgG relative to other plasma proteins. FcRn also recycles pathogenic IgG autoantibodies and is the tar...
The neonatal Fc receptor (FcRn) recycles immunoglobulin G (IgG) in cells and is responsible for the long half-life of IgG relative to other plasma proteins. FcRn also recycles pathogenic IgG autoantibodies and is the target for several new targeted therapeutic agents in IgG autoantibody-driven disorders. These therapeutics include rozanolixizumab, a high-affinity monoclonal antibody that directly blocks the IgG binding site on FcRn in a pH-independent manner. This study explored the impact of these molecular characteristics on rozanolixizumab's cellular uptake, endosomal trafficking and recycling. Another anti-FcRn therapeutic, the Fc fragment MST-HN IgG Fc (an analog of efgartigimod), a competitive antagonist with weaker affinity and pH-dependent binding to FcRn, was included for comparison. Using high-content imaging methods in human umbilical vein endothelial cells (HUVECs), a time- and concentration-dependent uptake of fluorescently labeled rozanolixizumab into intracellular compartments was observed. Uptake was rapid, pH-independent, and competed out with unlabeled inhibitor, supporting a receptor-mediated mechanism. Conversely, uptake of MST-HN IgG Fc was slower and required higher concentrations to detect uptake, which was pH-dependent, not competed out with unlabeled inhibitor, and occurred with similar potency in cells that did not express FcRn, suggesting a receptor-independent mechanism such as fluid phase pinocytosis. Using Rab proteins associated with different endosomal compartments, FcRn inhibitors appeared to traffic through recycling compartments in a similar manner in HUVECs, and their return to the cell surface in FcRn-transfected cells occurred with similar kinetics. These data demonstrate the impact of different structural features of FcRn inhibitors on functional outcomes on cells in vitro.
Exosome-mediated immune modulation in rheumatoid arthritis and its role in synovial inflammation and autoimmune amplification.
Kalidass B, Murugesan K, Shanmugam A … +2 more , Kaveri PK, Lakshmanan DK
Cell Immunol · 2026 Jun · PMID 42372468 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent articular inflammation, cartilage destruction and aberrant synovial angiogenesis. While current cytokine-centric therapies have revolu...
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent articular inflammation, cartilage destruction and aberrant synovial angiogenesis. While current cytokine-centric therapies have revolutionized RA management, their limitations highlight the need for a deeper understanding of the integrated synovial microenvironment. This review explores the critical role of exosomes as central regulatory nodes orchestrating intercellular communication within the RA joint. Under conditions of hypoxia and metabolic stress, exosomes secreted by fibroblast-like synoviocytes (FLS) and immune cells are dynamically loaded with pathogenic cargo, including microRNAs and autoantigens. These vesicles actively modulate macrophage phenotypes, moving beyond the traditional binary framework to reflect a continuum of pro-inflammatory activation, reprogram T-cells to favour pathogenic Th17 expansion while impairing regulatory T-cells (Tregs), and amplify autoreactive B-cell activation for sustained autoantibody production. While exosomes sustain the hypoxia-inflammation-angiogenesis axis and promote invasive pannus formation independently of transient soluble cytokines, we critically delineate which of these mechanisms are validated in RA-specific models against broader immunobiology. We propose that targeting these exosome-mediated signalling cascades offers a promising strategy to overcome therapeutic resistance, signifying their potential as novel therapeutic interventions and high-fidelity diagnostic biomarkers. Further, the significant translational, delivery, and standardization challenges are also addressed.
Persistent CD4 T cell hyporesponsiveness during recovery from prolonged symptomatic SARS-CoV-2 infection.
Ziegler J, Lawrence C, Pezant N … +11 more , Turner S, Redinger N, Guthridge C, Smith K, Chen J, Guthridge JM, James JA, Rankin S, Thompson LF, Farris AD, Kovats S
Cell Immunol · 2026 Jun · PMID 42320282 · Publisher ↗
Symptoms of acute SARS-CoV-2 infection often resolve quickly but are sometimes associated with persistent immune dysfunction. The factors that predispose individuals to compromised immune function have not been well defi...
Symptoms of acute SARS-CoV-2 infection often resolve quickly but are sometimes associated with persistent immune dysfunction. The factors that predispose individuals to compromised immune function have not been well defined. We investigated CD4 T cell phenotype and function in a small cohort of individuals who recovered from mild to moderate SARS-CoV-2 infection without hospitalization and were divided into short or prolonged symptom duration groups. Five individuals with prolonged symptom duration showed marked downregulation of CD4 on CD3CD8 T cells (CD4 group) and a poor response to TCR stimulation with the superantigen Staphylococcal enterotoxin B (SEB), as shown by weak upregulation of the activation markers CD134, CD25, CD279, and CD69. CD4 surface intensities recovered to normal levels in four of these individuals within 3-12 months. Selected cytokines (IL-1RA, IL-7, and VEGF) were elevated in individuals with low CD4, but plasma levels of anti-S1 IgG did not correlate with CD4 hyporesponsiveness. Bulk RNA sequencing of unstimulated and SEB-treated CD3CD8 T cells revealed a > 50% reduction in the number of differentially expressed genes in the CD4 group compared to the same individuals after CD4 levels were recovered and a healthy control group. Analyses of differentially expressed genes in unstimulated CD4 cells suggested a response to IFN, while SEB-stimulated CD4 cells showed reduced functionality of T cell activation, differentiation, and glycolysis pathways. In summary, in some individuals, prolonged symptomatic recovery from SARS-CoV-2 infection was associated with evidence of IFN signaling and transient reduction in CD4 expression accompanied by attenuated TCR activation by SEB.
Deficit in blood MAIT cells, altered cytokines and T cell dynamics in patients with coronary artery disease.
Stavridis D, Wacker M, Safarov R … +6 more , Testa N, Awad G, Varghese S, Borucki K, Wippermann J, Veluswamy P
Cell Immunol · 2026 May · PMID 42235192 · Publisher ↗
OBJECTIVES: Coronary artery disease (CAD) is a chronic inflammatory disorder characterized by immune dysregulation and a higher risk of viral infections. Among the immune cells involved, mucosal-associated invariant T (M...
OBJECTIVES: Coronary artery disease (CAD) is a chronic inflammatory disorder characterized by immune dysregulation and a higher risk of viral infections. Among the immune cells involved, mucosal-associated invariant T (MAIT) cells participate in antimicrobial defense and tissue repair, yet their contribution to CAD has not been clearly defined. METHODS: Peripheral blood mononuclear cells and plasma were obtained from patients with CAD and from healthy controls. MAIT cell subsets, conventional T cells, and the SARS-CoV-2 receptors ACE2 and CD147 were analyzed by flow cytometry. Cytokines were quantified using ELISA. Additional in-vitro assays were performed to test whether recombinant SARS-CoV-2 spike proteins could influence cell apoptosis or proliferation. RESULTS: The number of circulating MAIT cells was markedly reduced in CAD, most notably within the CD8 population. In contrast, CD4 MAIT cells were relatively increased but expressed less CCR5 intensities, suggesting limited migratory ability. Plasma IL-7 concentrations were lower in CAD, while IL-18 and IFN-α2 were higher. These findings indicate a disturbed cytokine environment, especially for MAIT cell activation. CAD samples also showed more CD4PD-1 and fewer CD8CD69 T cells, pointing toward an exhausted phenotype. IL-18 levels correlated negatively with left-ventricular ejection fraction. Expression of ACE2 and CD147 was similar between groups, and spike-protein exposure did not trigger significant apoptosis or proliferation in vitro. CONCLUSION: CAD is associated with loss and functional alteration of MAIT cells, cytokine imbalance, and T-cell exhaustion. Together, these immune changes may weaken antiviral defense mechanisms in the context of viral infections, such as the SARS-CoV-2 infection.
The circ_0003692-miR-1197-TLR4 axis: A key regulator in rheumatoid arthritis proliferation and inflammation.
Lu MA, Chen JZ, Shi Y … +2 more , Zheng CC, Lu L
Cell Immunol · 2026 May · PMID 42235191 · Publisher ↗
Rheumatoid arthritis (RA) is a joint disease characterized by abnormal development of fibroblast-like synoviocytes (FLSs). Circular RNAs (circRNAs) possess momentous regulatory functions in human disease progression. Thi...
Rheumatoid arthritis (RA) is a joint disease characterized by abnormal development of fibroblast-like synoviocytes (FLSs). Circular RNAs (circRNAs) possess momentous regulatory functions in human disease progression. This research was conducted to investigate regulatory mechanism of circ_0003692 in RA. In this research, circ_0003692 and Toll-like receptor 4 (TLR4) expressions were elevated in RA tissues and RA-fibroblast-like synoviocytes (RA-FLSs) (P < 0.05), but microRNA-1197 (miR-1197) level was decreased (P < 0.01). Functionally, circ_0003692 knockdown restrained RA-FLSs proliferation, inflammation, migration and invasion (P < 0.01). Mechanistically, miR-1197 was identified as a target for circ_0003692 and miR-1197 targeted TLR4. The expressions of circ_0003692 and TLR4 were positively correlated in RA, while miR-1197 and TLR4 expressions were negatively correlated in RA (P < 0.001). Rescue assay further authenticated that interference with circ_0003692 reduced RA-FLSs proliferation and inflammation through miR-1197/TLR4/nuclear factor-transcription factor B (NF-κB) (P < 0.05). In vivo research also vindicated that circ_0003692 knockdown alleviated CIA mice by reducing synovial tissue proliferation and inflammatory cell infiltration, relieving cartilage injury and reducing osteoclast formation in CIA mice (P < 0.05). In summary, interference with circ_0003692 reduced RA-FLSs proliferation and inflammation via miR-1197/TLR4/NF-κB.
IGF2BP2 promotes cuproptosis of cardiomyocytes through mA modification of MAP2K1 in sepsis-induced myocardial injury.
Chen R, Lu L, Lin B … +2 more , Chen C, Liang Y
Cell Immunol · 2026 Jul · PMID 42167092 · Publisher ↗
BACKGROUND: Sepsis-induced myocardial injury (SIMI) has become an important cause of death in septic patients, and it is a multi-faceted pathophysiological process. The present study aims to understand how insulin-like g...
BACKGROUND: Sepsis-induced myocardial injury (SIMI) has become an important cause of death in septic patients, and it is a multi-faceted pathophysiological process. The present study aims to understand how insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) regulates cardiomyocyte cuproptosis through an mA-dependent regulation of mitogen-activated protein kinase kinase 1 (MAP2K1), and advance our knowledge of SIMI. METHODS: In vivo and in vitro SIMI models were developed through lipopolysaccharide (LPS) administration in mice and AC16 cardiomyocytes, respectively. The functions of IGF2BP2 and MAP2K1 in regulating cuproptosis under septic myocardial injury were explored through loss- and gain-of-function approaches. Furthermore, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) experiments as well as actinomycin D experiments confirmed the regulatory interaction of IGF2BP2 with MAP2K1. RESULTS: In SIMI models, the IGF2BP2 mRNA and protein expressions were all significantly upregulated, accompanied by myocardial pathological damage and poor cardiac function. Knockdown of IGF2BP2 considerably lessened LPS-induced myocardial injury, lowered copper levels in serum and myocardial tissue, and rectified the changed expression of key cuproptosis-related proteins such as MAP2K1, solute carrier family 31 member 1 (SLC31A1), ferredoxin 1 (FDX1), heat shock protein 70 (HSP70), dihydrolipoamide S-acetyltransferase (DLAT), and lipoyl synthase (LIAS). Mechanistically, IGF2BP2 interacts with MAP2K1 mRNA to improve the mRNA stability and protein expression of MAP2K1 through N6-Methyladenosine (mA) modification. In addition, overexpression of MAP2K1 abrogated the suppressive effects of IGF2BP2 knockdown on cardiomyocyte cuproptosis. CONCLUSION: IGF2BP2 improves MAP2K1 expression stability via mA modification, which promotes cardiomyocyte cuproptosis and worsens SIMI. This mechanism might give some possible therapy targets for curing septic myocardium injury.
MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance.
Liu Y, Qi F, Zeng H … +6 more , Huang D, Zhang W, Zhang Y, Gong J, Xiang L, Yi Z
Cell Immunol · 2026 Jul · PMID 42061114 · Publisher ↗
Increasing evidence highlights the crucial role of endotoxin tolerance in the regulation of the sepsis, yet its underlying mechanisms remain poorly understood. Here, we provide evidence to support a novel role for the mi...
Increasing evidence highlights the crucial role of endotoxin tolerance in the regulation of the sepsis, yet its underlying mechanisms remain poorly understood. Here, we provide evidence to support a novel role for the mitochondrial pyruvate carrier1 (MPC1)-mediated mitochondrial oxidative stress resistance in regulation of endotoxin tolerance in macrophages. We observed decrease expression of MPC1 in macrophages of sepsis models both in vitro and in vivo, while LPS-tolerant macrophages exhibited increased MPC1 levels. Overexpression of MPC1 significantly reduced LPS-induced inflammatory responses and oxidative stress, suggesting its anti-inflammatory properties. Intriguingly, we found that overexpression of MPC1 did not foster endotoxin tolerance in macrophages. Furthermore, Overexpression of MPC1 inhibited mitochondrial oxidative stress resistance mediated by mitochondrial reactive oxygen species (mtROS), which weakened the resistance of macrophages to LPS secondary stimulation, and then inhibited endotoxin tolerance. Despite mtROS typically acting as pro-inflammatory mediators, our findings indicate that mtROS which regulated via the SIRT3/SOD2 pathway, is essential for MPC1's control over mitochondrial oxidative stress resistance and endotoxin tolerance. Collectively, these findings uncover a novel mechanism through which MPC1 modulates inflammation and induces endotoxin tolerance, underscoring the potential of targeting MPC1 in sepsis treatment.
Beyond HLA-Ia: A multidimensional framework for Neoantigen immunotherapy.
Ding L, Guo C, Qin Y … +2 more , Wu L, Wei P
Cell Immunol · 2026 Jul · PMID 42061113 · Publisher ↗
Glioblastoma (GBM) and other malignant gliomas are associated with aggressive progression, high recurrence rates, and poor long-term outcomes, while current standard therapies provide limited survival benefit. Neoantigen...
Glioblastoma (GBM) and other malignant gliomas are associated with aggressive progression, high recurrence rates, and poor long-term outcomes, while current standard therapies provide limited survival benefit. Neoantigen-based immunotherapy offers tumor specificity but is severely restricted in gliomas by HLA-Ia downregulation, pronounced intratumoral heterogeneity, an immunosuppressive tumor microenvironment, and the blood-brain barrier (BBB). In this review, we summarize recent advances and propose a multidimensional framework to address these barriers. Specifically, we discuss the potential use of HLA-E as an alternative antigen-presentation platform, γδ T cells as complementary effector populations capable of partially bypassing classical HLA-Ia dependence, artificial intelligence-assisted neoantigen prioritization and optimization, and emerging BBB-penetrating delivery technologies. Together, these strategies uncouple neoantigen targeting from individual HLA restrictions, establishing a "genotype-agnostic" foundation. Ultimately, this integrated framework aims to develop broadly applicable, off-the-shelf neoantigen immunotherapies, improving translational feasibility and providing new directions for overcoming immune escape in gliomas.
Silibinin restricts mitochondria-associated inflammatory pathways in LPS-stimulated murine microglia BV2 through TREM2.
Chen W, Wang X, Liu P … +7 more , Kang Y, Hayashi T, Mizuno K, Hattori S, Fujisaki H, Liu W, Ikejima T
Cell Immunol · 2026 Jul · PMID 41996954 · Publisher ↗
Microglia are resident immune cells in the central nervous system mediating brain inflammatory responses. The flavonoid silibinin has been found to restrict the neuronal inflammatory conditions in vivo. To fully reveal t...
Microglia are resident immune cells in the central nervous system mediating brain inflammatory responses. The flavonoid silibinin has been found to restrict the neuronal inflammatory conditions in vivo. To fully reveal the underlying mechanisms, effects of silibinin on neuroinflammation was evaluated in lipopolysaccharides (LPS)-stimulated murine microglia BV2. The increased NO level, and the up-regulated pro-inflammatory proteins including iNOS and COX-2 in LPS-treated cells were all restricted by the treatment with silibinin. Further investigation showed that, mitochondrial disorders caused by LPS, including the excessive fission, loss of mitochondrial membrane potentials and intracellular ATP levels, augmented ROS and oxidative damages of mitochondrial DNA (mtDNA), were all attenuated by the treatment with silibinin. The protective effect of silibinin against the STING and NLRP3 inflammasome pathways is attributed to its ability to restore mitochondrial quality control. Of note, triggering receptors expressed on myeloid cells 2 (TREM2), a transmembrane receptor important for modulating microglia-associated inflammation, was low in LPS-treated cells but largely preserved in cells co-treated with silibinin. Molecular docking results show that silibinin has a binding potential with TREM2, which has also been confirmed in CETSA assay. TREM2 knockdown in microglia promotes a proinflammatory phenotype and mitochondrial damage which was reversed with silibinin treatment by increasing the stability of TREM2. Our data show that silibinin reduces mitochondrial damage and proinflammatory activation in microglia through the stabilization of TREM2. These results highlight the potential of silibinin as a treatment in neuroinflammatory diseases.
MFG-E8 inhibits AT1-AA production to alleviate preeclampsia.
Xie F, Shi Z, Zhu J … +3 more , Lin C, Zhou Y, Lin F
Cell Immunol · 2026 Jul · PMID 41996953 · Publisher ↗
PURPOSE: Preeclampsia (PE) is a multifactorial disease, in which immune dysregulations especially pathogenic autoantibody AT1-AA is critically involved. MFG-E8 deficiency can lead to autoimmune disorders, yet its role in...
PURPOSE: Preeclampsia (PE) is a multifactorial disease, in which immune dysregulations especially pathogenic autoantibody AT1-AA is critically involved. MFG-E8 deficiency can lead to autoimmune disorders, yet its role in AT1-AA-mediated PE remains unclear. Thus, this study explores whether MFG-8 inhibits AT1-AA production by promoting macrophage phagocytosis of apoptosis trophoblasts. METHODS: Placental MFG-E8 expression, trophoblast apoptosis, and serum levels of TNF-α, sFlt-1, and AT1-AA were detected between PE patients and healthy subjects. The LPS-induced PE rat models and trophoblast-macrophage co-culture system were established to evaluate the effects of MFG-E8 on AT1-AA production and macrophage phagocytic function. RESULTS: Reduced placental MFG-E, increased trophoblast apoptosis, and elevated serum levels of TNF-α, sFlt-1, and AT1-AA were detected in PE patients. MFG-E8 administration attenuated PE symptoms in rats, reduced AT1-AA expressions, and promoted macrophage clearance of apoptotic trophoblasts and AT1R antigen in vitro. CONCLUSION: MFG-E8 alleviates PE progression by promoting macrophage phagocytosis of apoptotic trophoblasts and inhibiting AT1-AA production.
UVB induces DNA hypomethylation and cell activation in CD4 T cells of systemic lupus erythematosus via miR-410 regulating GADD45A.
Cai Z, Cheng ZL, Tan YN … +12 more , Meng XW, Jiang GG, Lu ZY, Jin L, Sun XG, Wang X, Li-Sun, Xiang-Yuan, Li XX, Li YW, Jia XY, Zhang M
Cell Immunol · 2026 Jul · PMID 41967432 · Publisher ↗
OBJECTIVE: To explore the impact of ultraviolet B (UVB) on the DNA methylation and activation in CD4 T cells of systemic lupus erythematosus (SLE) patients and the underlying mechanisms. METHODS: CD4 T cells were isolate...
OBJECTIVE: To explore the impact of ultraviolet B (UVB) on the DNA methylation and activation in CD4 T cells of systemic lupus erythematosus (SLE) patients and the underlying mechanisms. METHODS: CD4 T cells were isolated and separated from both healthy controls (HCs) and SLE patients, then exposed to 100 mJ/cm UVB. CD4 T cell activation and DNA methylation levels were assessed by RT-qPCR and ELISA. PBMC sequencing data and CD4 T cell expression data from the GEO platform were used to analyze the expression of GADD45A. RT-qPCR was utilized to measure the levels of miR-410, GADD45A, and CD70 before and after UVB exposure. GADD45A protein expression levels were detected by Western blot. Dual-luciferase reporter gene assay was used to analyze the relationship between miR-410 and GADD45A. SLE CD4 T cells were transfected with miR-410 mimics, and GADD45A, DNA methylation, and cell activation levels were measured after UVB irradiation. RESULTS: At baseline, SLE patients showed significantly higher levels of DNA hypomethylation and activation in CD4 T cells compared to HCs, these effects were further enhanced after exposure to UVB. MiR-410 was downregulated in SLE CD4 T cells, while GADD45A showed high expression levels. Dual luciferase reporter gene experiments showed that miR-410 directly downregulates GADD45A. Overexpression of miR-410 can consequently downregulate the expression levels of GADD45A, improve the DNA hypomethylation and cell activation induced by UVB. CONCLUSION: These results suggest that miR-410 targets and negatively regulates GADD45A, thereby involving in UVB-induced cell activation and DNA hypomethylation in SLE CD4 T cells.
WISP-3 enhances proinflammatory cytokine IL-1β production in rheumatoid arthritis through the FAK, JNK and AP-1 pathways.
Hou SM, Wang GS, Guo JH … +4 more , Liu CL, Chen CJ, Tang CH, Lin CY
Cell Immunol · 2026 Jul · PMID 41955703 · Publisher ↗
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and long-term disability. Interleukin-1β (IL-1β) is a key pro-inflam...
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and long-term disability. Interleukin-1β (IL-1β) is a key pro-inflammatory cytokine implicated in RA pathogenesis. Wnt1-inducible signaling pathway protein 3 (WISP-3) has been associated with joint homeostasis and RA development, but the molecular mechanisms by which WISP-3 regulates synovial inflammation remain poorly understood. METHODS: In this in vitro study, human RA synovial fibroblasts (RASFs) were treated with increasing concentrations of WISP-3 to evaluate IL-1β expression at both mRNA and protein levels. The involvement of focal adhesion kinase (FAK), c-Jun N-terminal kinase (JNK), and c-Jun signaling was investigated using pharmacological inhibitors and siRNA-mediated gene silencing. Protein phosphorylation and transcriptional activity were assessed to delineate the signaling cascade. RESULTS: WISP-3 significantly upregulated IL-1β expression in a dose-dependent manner. Mechanistic analyses demonstrated that WISP-3 activated FAK, which in turn induced phosphorylation of JNK and c-Jun. This signaling cascade enhanced transcriptional activity and promoted IL-1β production. Blockade of FAK, JNK, or c-Jun, either by selective inhibitors or siRNA-markedly attenuated WISP-3-induced IL-1β expression, confirming that the FAK/JNK/c-Jun axis plays a major role in WISP-3-induced IL-1β expression. CONCLUSION: These in vitro findings indicate that WISP-3 acts as a pro-inflammatory mediator in RA by promoting IL-1β expression primarily through activation of the FAK/JNK/c-Jun pathway, with additional contributions from other signaling pathways.
Armed oncolytic adenovirus elicits a "self-feeder" effect to supercharge NK cells for solid tumor control.
Liao Q, Lai S, Fan Z … +7 more , Li N, Zou B, Han M, Peng Y, Wu J, Xun J, Tan X
Cell Immunol · 2026 · PMID 41932099 · Publisher ↗
BACKGROUND: Natural killer (NK) cells are pivotal effectors in innate anti-tumor immunity, but their efficacy against solid tumors is constrained by inadequate tumor infiltration and functional suppression within the tum...
BACKGROUND: Natural killer (NK) cells are pivotal effectors in innate anti-tumor immunity, but their efficacy against solid tumors is constrained by inadequate tumor infiltration and functional suppression within the tumor microenvironment (TME). Although ex vivo expansion increases NK cell numbers, poor tumor homing and transient post-infusion activity persist as major limitations. This work aims to develop a combinatorial approach integrating ex vivo NK cell expansion with localized immunomodulation via engineered oncolytic adenoviruses (oAds) to address these challenges. METHODS: K562 feeder cells were engineered to stably express IL-2, membrane-bound IL-21 (mbIL-21), and 4-1BBL to activate and expand NK cells ex vivo. Following irradiation, these cells were used to expand NK cells ex vivo. Armed oAds (oAd-IL-2/mbIL-21/4-1BBL) were designed to express IL-2, mbIL-21, and 4-1BBL. In vitro assays were used to evaluate the impact of oAd-IL-2/mbIL-21/4-1BBL on tumor cell lysis, as well as NK cell proliferation, activation, and migration. A HCT116 subcutaneous tumor-bearing mouse model was used to assess the combined anti-tumor effects of ex vivo-expanded NK cells and oAd-IL-2/mbIL-21/4-1BBL, focusing on tumor growth inhibition and NK cell infiltration in tumor lesions. RESULTS: We firstly constructed K562 feeder cells stably co-express IL-2, mbIL-21, and 4-1BBL, enabling 100-fold NK cell expansion (>85% purity) within 14 days. Concurrently, armed oAds were engineered to deliver these immunomodulators. oAd-IL-2/mbIL-21/4-1BBL enhanced NK cell proliferation, activation, migration, and tumor cell lysis in vitro. In HCT116 colorectal xenograft models, combing ex vivo-expanded NK cells with oAd-IL-2/mbIL-21/4-1BBL synergistically suppressed tumor growth and increased tumor-infiltrating NK cells. Mechanistically, oAds elicited a "self-feeder" effect through localized immunomodulator production, sustaining NK cell activity within the TME. CONCLUSIONS: These findings define a dual-phase strategy that integrate scalable ex vivo expansion with in situ activation to overcome key barriers in NK cell therapy for solid tumors.
Tumor resection may abort the antitumor immune response produced from primary foci.
Xu K, Zhao B, Mei J … +4 more , Yuan H, Xue J, Feng F, Liu F
Cell Immunol · 2026 · PMID 41916199 · Publisher ↗
Clinical observations suggest that after surgical removal of the primary tumor, metastases exhibit accelerated growth. This suggests that the primary tumor may exert inhibitory effects on micrometastases, and its surgica...
Clinical observations suggest that after surgical removal of the primary tumor, metastases exhibit accelerated growth. This suggests that the primary tumor may exert inhibitory effects on micrometastases, and its surgical removal may conversely become a factor that is unfavorable for antitumor therapy. Proposed over a century ago, this phenomenon is linked to antitumor immune responses, known as concomitant immunity (CI), wherein the primary tumor suppresses secondary tumors through specific immune mechanisms. Subsequent studies have investigated the patterns and mechanisms of CI, facilitating the development of novel targets and treatment strategies for suppressing metastasis. This review traces the evolution of CI theory, summarizes the latest mechanisms underlying its antitumor effects, examines how surgery disrupts CI, and discusses current therapeutic approaches leveraging CI principles. This review focuses on CI to provide a theoretical basis for understanding postoperative recurrence mechanisms and developing novel anti-metastatic strategies.
The RNA-binding protein ALYREF promotes mitochondrial dysfunction and ferroptosis in CD4 helper T cells in chronic obstructive pulmonary disease and non-small cell lung cancer by enhancing ZWINT mRNA stability.
Li S, Song Q, Dong F … +3 more , Liu H, Meng S, Hu X
Cell Immunol · 2026 · PMID 41911658 · Publisher ↗
BACKGROUND AND AIMS: Immune dysfunction in the tumor microenvironment contributes to the progression of non-small cell lung cancer (NSCLC) in patients with chronic obstructive pulmonary disease (COPD). This study aimed t...
BACKGROUND AND AIMS: Immune dysfunction in the tumor microenvironment contributes to the progression of non-small cell lung cancer (NSCLC) in patients with chronic obstructive pulmonary disease (COPD). This study aimed to elucidate the roles of the RNA-binding protein Aly/REF export factor (ALYREF) and its target, ZW10 interacting protein (ZWINT), in mediating CD4 T cell dysfunction in this context. METHODS: A murine model of COPD-associated NSCLC was established, and an in vitro system simulating the disease microenvironment was built. Primary CD4 T cells underwent genetic knockdown or overexpression of ALYREF and ZWINT for functional analyses and adoptive transfer experiments. The interaction between ALYREF and ZWINT was investigated using RNA immunoprecipitation and mRNA stability assays. T cell mitochondrial function and ferroptosis were assessed by flow cytometry. RESULTS: ALYREF and ZWINT were significantly upregulated in COPD-associated NSCLC tumors. ALYREF directly bound to ZWINT mRNA, enhancing its stability and increasing its expression. This upregulation drove CD4 T cell mitochondrial dysfunction and ferroptosis. Adoptive transfer of T cells overexpressing ZWINT accelerated tumor growth in vivo, an effect that was mitigated by silencing ALYREF. CONCLUSION: The ALYREF-ZWINT axis promotes CD4 T cell ferroptosis, contributing to an immunosuppressive microenvironment and facilitating tumor progression in COPD-associated NSCLC. Targeting this pathway represents a novel therapeutic strategy to restore anti-tumor immunity.
FGF20 alleviates neuroinflammation in ischemic stroke by modulating microglial polarization via TREM2-TLR4/NF-κB pathway.
Zhu L, Guo S, Wang Z … +6 more , Huang M, Liu M, Ruan L, Zou Y, Lin L, Wang X
Cell Immunol · 2026 · PMID 41819663 · Publisher ↗
Microglia play dual roles in neuroinflammation, driving either detrimental M1 or protective M2 polarization, which critically impacts the outcomes of ischemic stroke. While fibroblast growth factor 20 (FGF20) is establis...
Microglia play dual roles in neuroinflammation, driving either detrimental M1 or protective M2 polarization, which critically impacts the outcomes of ischemic stroke. While fibroblast growth factor 20 (FGF20) is established as a neurotrophic factor with neuroprotective properties, its role in regulating microglial polarization remains unclear. This study investigated a novel function of FGF20 in alleviating post-stroke neuroinflammation and its underlying mechanisms. In a rat model of middle cerebral artery occlusion (MCAO), intracerebroventricular administration of FGF20 significantly reduced infarct volume and improved neurological function. RT-PCR analysis revealed that FGF20 bidirectionally regulated cytokine expression, suppressing M1-associated markers (CD86, IL-1β, IL-6, iNOS, TNF-α) while enhancing M2-associated markers (IL-10, Arg-1). Immunofluorescence staining demonstrated that FGF20 attenuated microglia activation in peri-infarct striatum and hippocampus. In vitro, FGF20 counteracted LPS-induced M1 polarization in primary microglia, downregulated the TLR4/NF-κB pathway, and upregulated TREM2 expression. Notably, while the selective FGFR1 inhibitor PD173074 abolished FGF20-induced TREM2 upregulation, it did not reverse the suppression of TLR4/NF-κB, indicating that these two effects are mediated through distinct regulatory mechanisms. These phenotypic shifts were further confirmed by a reduction in CD32/16 (M1) cells and an increase in Arg1 (M2) cells. Mechanistically, FGF20 restored the balance between TREM2 and TLR4 signaling, inhibiting NF-κB activation and attenuating neuroinflammatory responses. Collectively, our findings identify FGF20 as a novel dual modulator of microglial polarization that integrates TREM2-mediated immunoregulation with FGFR1-dependent and independent suppression of TLR4/NF-κB pathway. Thus, FGF20 represents a promising therapeutic candidate for ischemic stroke, extending its functional profile from neuroprotection to targeted immunomodulation through phenotype-specific regulation of microglial polarization.
Corrigendum to "BCG and β-glucan primed monocytes yield dendritic cells that hamper the induction of pro-inflammatory T cell immunity" [Cell. Immunol. 419 (2026) 105060].
Cuenca-Escalona J, Kramer R, Marjalizo-Jimenez C … +5 more , Domínguez-Andrés J, Netea MG, Flórez-Grau G, de Vries IJM, Horrevorts SK
Cell Immunol · 2026 · PMID 41813464 · Publisher ↗
Abstract loading — click title to view on PubMed.
STAT signaling pathway in pregnancy stages and related to complications.
Aslanian-Kalkhoran L, Abbas-Kabiri D, Afandideh F … +3 more , Badihi E, Shahabirad R, Yousefi M
Cell Immunol · 2026 Apr · PMID 41762776 · Publisher ↗
Signal transducer and activator of transcription (STAT) proteins are essential DNA-binding proteins that not only facilitate signal transduction but also play a critical role in regulating gene transcription, making them...
Signal transducer and activator of transcription (STAT) proteins are essential DNA-binding proteins that not only facilitate signal transduction but also play a critical role in regulating gene transcription, making them vital for cellular communication and response. Considering the role of this protein in biological processes such as proliferation, differentiation, and inflammation, its significance in the reproductive system, particularly during pregnancy, is undeniable. STAT signaling is essential for controlling embryonic implantation and endometrial decidualization during pregnancy, ensuring the building and preservation of maternal-fetal immune tolerance. Recent studies suggest a role for STAT in pregnancy-related issues such as implantation failure (IF), spontaneous abortion (SA), gestational diabetes mellitus (GDM), and preeclampsia (PE). This study aims to evaluate the mechanisms of STAT signaling in maintaining normal pregnancy processes and the complication related to its dysregulation, in order to propose appropriate therapeutic approaches based on this signaling.
Dendritic cells targeted CEA tumor antigen through DEC205 in combination with oncolytic reovirus stimulate strong immune response in colorectal cancer model.
Hajiahmadi N, Tenbusch M, Malekshahi SS … +3 more , Yari A, Moazzeni SM, Bamdad T
Cell Immunol · 2026 Apr · PMID 41747397 · Publisher ↗
BACKGROUND: Colorectal cancer is one of the most common cancers worldwide. Current treatments, including surgery, chemotherapy, and radiotherapy, have limitations due to their non-specific action, drug resistance, and in...
BACKGROUND: Colorectal cancer is one of the most common cancers worldwide. Current treatments, including surgery, chemotherapy, and radiotherapy, have limitations due to their non-specific action, drug resistance, and inability to induce memory immune responses. The use of combination therapies for effective treatments appears to be more effective. In this study, the single and combined anti-tumor effects of immunotherapy targeting the CEA tumor antigen to dendritic cells and virotherapy with Reovirus were investigated in a mouse colorectal cancer model. METHOD: A recombinant adenovirus expressing the CEA gene fused to DEC205 was constructed to target dendritic cells (DCs). The single and combined effects of immunotherapy and virotherapy together with PD1/PDL1 inhibitor, lenalidomide, and CEA CT26 necrotic cells as adjuvants in the treatment of colorectal tumor models, were evaluated by assessing tumor growth, histological changes, and immune responses. The prophylactic effects of CEA immunization were also investigated. RESULTS: Under pre-treatment conditions, CEA-targeted DCs, along with all three adjuvants, significantly reduced tumor growth (p-value<0.05) and enhanced cellular immune responses compared to the untreated group. Immunotherapy alone and in combination with virotherapy in tumor-bearing mice produced a stronger antitumor effect when injected with each of the three adjuvants compared to the untreated group. CONCLUSION: CEA-targeted immunotherapy and immune-virotherapy induced potent antitumor immune responses. Considering all measured parameters, there was not enough evidence to support the superiority of any single adjuvant; however, lenalidomide in combination therapy enhanced specific immune and antitumor effects. All the combination protocols used in this study were able to induce a strong antitumor immunity, and could be further optimized with additional adjunctive therapies for complete tumor remission.
Identification and validation of hub genes associated with neutrophil immunosuppression during Sepsis.
Zhang R, Kan Y, Liu H … +5 more , Pan P, Hu X, Xu Y, Wang J, Wang J
Cell Immunol · 2026 Apr · PMID 41740292 · Publisher ↗
OBJECTIVE: Sepsis involves a transition from hyperinflammation to immunosuppression, with neutrophils playing a central role in both phases. However, the molecular basis of neutrophil-driven immunosuppression remains unc...
OBJECTIVE: Sepsis involves a transition from hyperinflammation to immunosuppression, with neutrophils playing a central role in both phases. However, the molecular basis of neutrophil-driven immunosuppression remains unclear. This study aimed to identify and validate hub genes regulating neutrophil immunosuppression in sepsis to uncover potential therapeutic targets. METHODS: Neutrophil transcriptomic datasets (GSE64457, GSE180387) from the GEO database were analyzed using WGCNA to identify modules correlated with sepsis progression, followed by GO/KEGG enrichment and PPI network construction. Candidate hub genes were validated through single-cell RNA sequencing of human peripheral blood neutrophils. A cecal ligation and puncture (CLP) murine sepsis model was further used to evaluate neutrophil-mediated immunosuppression via CD4 T cell co-culture assays, with hub gene expression confirmed by Western blot analysis and qPCR. RESULTS: WGCNA identified immune-related modules strongly associated with sepsis progression, enriched in cytokine signaling, immune receptor activity, and neutrophil degranulation. Intersection analysis revealed 34 common genes, and PPI networks prioritized three hub genes: NFKBIZ, TNFAIP2, and CTSS. Single-cell analysis demonstrated distinct expression of these hub genes in immunosuppressive versus non-immunosuppressive neutrophils. In the CLP model, late-stage neutrophils (day 5) significantly suppressed CD4 T cell proliferation compared to early-stage neutrophils (day 1, p < 0.01). Protein validation confirmed upregulation of NFKBIZ and downregulation of TNFAIP2 and CTSS in late-stage sepsis. CONCLUSION: Integrated bioinformatics and experimental validation identified NFKBIZ, TNFAIP2, and CTSS as potential regulators of neutrophil immunosuppression in sepsis. Their dynamic expression highlights key mechanistic features associated with immune dysfunction and suggests new targets for reversing sepsis-induced immunoparalysis.
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