Search Results (1,533)

PRMT5, a type II methyltransferase catalyzing symmetric dimethylation of arginine residues, has emerged as a promising therapeutic target in various cancers. However, the precise mechanism by which PRMT5 mediated the tumor immune microenvironment, particularly CD8⁺ T cell recruitment in cervical cancer remains elusive. Analysis of data from The Cancer Genome Atlas (TCGA) revealed elevated PRMT5 mRNA levels in cervical cancer tissues, which correlated with reduced immune cell infiltration and poorer patient prognosis. To further investigate the role of PRMT5 in tumor development, a CD8 knockout (KO) mouse tumor model was utilized. Significant inhibition of tumor growth was observed in cervical cancer using a mouse model lacking PRMT5. Notably, this antitumor effect was attenuated in CD8 KO mice lacking functional CD8⁺ T cells. Mechanistically, RNA sequencing (RNA-seq) analysis was conducted to explore how PRMT5 regulates immune cell recruitment. Disruption of PRMT5 was found to increase the secretion of chemokine CXCL10 by tumor cells. CXCL10 binds to its receptor CXCR3, thereby recruiting T cells to the tumor. Furthermore, in CXCR3 KO mice, PRMT5 knockdown failed to enhance T cell infiltration into tumors. These findings indicate that PRMT5 knockdown promotes CD8⁺ T cell recruitment to the tumor microenvironment via CXCL10 signaling. Furthermore, the therapeutic efficacy of the selective PRMT5 inhibitor EPZ015666 was evaluated in a cervical cancer xenograft mouse model. Treatment with EPZ015666 effectively suppressed tumor growth. In summary, these findings elucidate a novel mechanism whereby PRMT5 depletion in cervical cancer cells triggers a CXCL10-mediated chemotactic response, enhancing CD8⁺ T cell infiltration and restricting tumor progression. Thus, our study provides compelling evidence supporting the potential targeting of PRMT5 as a viable immunotherapeutic strategy for cervical cancer. Full article

PANoptosis is an integrated form of regulated cell death that combines pyroptosis, apoptosis, and necroptosis through a coordinated molecular platform known as the PANoptosome. Autophagy, in parallel, maintains immune homeostasis by controlling cellular stress responses. Although both pathways are essential for innate and adaptive immunity, their functional interplay has only recently been explored. This review summarizes current knowledge on the bidirectional relationship between PANoptosis and autophagy, with emphasis on how autophagy can restrain PANoptotic signaling or, under certain conditions, promote inflammatory cell death. We discuss cell-type-specific aspects of this crosstalk in macrophages, dendritic cells, monocytes, neutrophils, T cells, and B cells, focusing on key PANoptosis mediators and autophagy-related proteins. We then examine how dysregulated autophagy and exaggerated PANoptotic signaling contribute to chronic inflammation and tissue damage in immune-mediated inflammatory disease, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, psoriasis, and inflammatory bowel disease. Finally, we outline shared molecular principles that position the autophagy–PANoptosis axis as a fundamental immunoregulatory mechanism and a promising source of therapeutic targets in chronic inflammatory and autoimmune disorders. Full article

Background/Objectives: Melanoma is a highly malignant skin tumor with poor response to conventional chemotherapeutic regimens. Melanoma cells induce cytotoxic T cell-mediated immune responses, and immunotherapy has significantly improved survival rates for patients with advanced disease. Methods: Here, we investigate NK cell-mediated melanoma cell killing and its regulation by PD-L1/PD-1 blockade and IFNβ. Four melanoma cell lines were used in this study. To evaluate NK cell cytotoxicity, cells were exposed to NK cells with or without IFNβ. The calcein release assay was used to measure cell death, while specific inhibitors and siRNA silencing were applied to determine the contribution of individual effector pathways. Results: NK cells were able to kill melanoma cells with sensitivity to killing varying between different cell lines. Cytotoxic effects were mainly mediated through activation of the TRAIL signaling cascade. In cell lines with low sensitivity to NK cell killing, expression of PD-L1 was noted and killing by NK cells could be significantly increased by inhibition of the PD-L1/PD-1 checkpoint. Killing of melanoma cells could be further increased by incubation of NK cells with IFNβ. Conclusions: Our results point to a role of NK cells in the killing of melanoma cells and a potential clinical benefit of a combination therapy of IFNβ and anti-PD-1 antibody. Full article

Diabetic kidney disease (DKD) is a major complication of type 2 diabetes mellitus (T2DM) and a leading cause of morbidity and mortality. Both metabolic and inflammatory pathways have emerged as potential sources of biomarkers that may improve DKD detection and treatment. This study investigated the relationship between gut-derived metabolites, such as acylcarnitines (ACs), uremic toxins (UTs), polyol pathway intermediates (PIs), and amino acid derivatives (AADs), and renal inflammation markers, detected in serum and urine. It included 20 healthy controls and 90 patients with T2DM, divided into normoalbuminuria, microalbuminuria, and macroalbuminuria. Serum and urine metabolites were analyzed using untargeted and targeted metabolomic assessments, whereas inflammatory markers were quantified using the ELISA technique. Statistical analysis consisted of descriptive statistics followed by univariable and multivariable linear regression analyses. Our findings revealed that serum AADs contribute to renal fibrosis progression, whereas urinary AADs indicate impaired tubular reabsorption in inflammatory conditions. Additionally, UTs and PIs are linked to inflammatory processes mediated by TNF-α but not by early renal fibrosis, whereas serum ACs appear to modulate immune responses, exerting pro-inflammatory and cytotoxic effects on tubular epithelial cells in early DKD. Thus, the metabolic and inflammatory pathways are tightly interconnected and synergistically contribute to the pathogenesis of early DKD. Full article

Background/Objectives: Varicella-zoster virus (VZV) causes herpes zoster (HZ/shingles), particularly in older adults with weakened cell-mediated immunity (CMI), which is essential for controlling VZV reactivation and reducing HZ severity. Currently vaccines, like recombinant subunit or live-attenuated vaccine, showed shortcomings in eliciting CD8⁺ T-cell responses. Addressing this, we utilized the novel replication-defective chimpanzee adenovirus vector ChAdOx1 to construct the ChAdOx1-VZV (CVE) vaccine, using full-length glycoprotein E (gE) as antigen. This study evaluated the immunogenicity of a heterologous intramuscular (IM) prime/intranasal (IN) boost regimen with the aim of developing a novel VZV vaccine candidate. Methods: BALB/c mice were immunized with CVE using homologous or heterologous prime-boost regimens via IM or IN. And cynomolgus macaques were immunized intramuscularly with three doses of CVE. Cellular responses were assessed by intracellular cytokine staining (ICS) and IFN-γ ELISpot using splenocytes and PBMCs. Humoral responses were evaluated by serum gE-IgG ELISA and bone-marrow LLPC ELISpot. Memory subsets and tissue-resident T cells were analyzed by flow cytometry. Results: Heterologous IM prime/IN boost CVE regimen markedly enhanced both cellular and humoral responses, especially CD8⁺ T-cell responses. The induced LLPC and memory T cell responses indicate the potential for long-term protection against herpes zoster. In cynomolgus macaques, CVE induced robust serum gE-specific IgG responses and strong IFN-γ secreting T-cell activity, supporting the immunogenicity of CVE in a genetically distinct primate model and enhancing its clinical translational potential. Conclusions: CVE induces potent cellular and humoral immunogenicity, with IM prime/IN boost vaccination. Cross species immunogenicity observed in nonhuman primates further strengthens the translational relevance of this platform. These findings support CVE as a promising herpes zoster vaccine candidate and provide a rationale for continued evaluation in human-relevant systems. Full article

Extracellular vesicles, encompassing eukaryotic exosomes and bacterial outer membrane vesicles (OMVs), play multifaceted roles in mediating host–pathogen interactions. These nanoscale structures act as critical mediators of intercellular communication, transporting diverse bioactive cargo such as miRNAs, cytokines, proteins, and bacterial components. Exosomes contribute to host immunity by delivering antimicrobial agents and modulating inflammatory responses, but they can also be hijacked by pathogens to suppress defenses and promote persistent infection. OMVs, on the other hand, enable bacteria to disseminate virulence factors, deliver toxins directly into host cells, and modulate immune signaling. For example, exosomes from infected macrophages can stimulate dendritic cell activation and T-cell priming, whereas bacterial OMVs have been shown to suppress host immunity or trigger excessive inflammation depending on their molecular cargo. Importantly, OMVs facilitate horizontal gene transfer and nutrient exchange within microbial communities, thereby influencing microbiome composition and adaptation. Together, these complex dynamics position both exosomes and OMVs as central players in immunity and pathogenesis. This review synthesizes recent insights into how host- and pathogen-derived vesicles modulate infection biology and immune responses, while also exploring their potential as diagnostic biomarkers and therapeutic carriers, and discussing current limitations in their clinical translation. Full article

Background and Objectives: MGN-3/Biobran (BRM4, Lentin Plus or Ribraxx) is a natural, rice bran-derived arabinoxylan immunoceutical that modulates the adaptive immune response to viral infections. In response to bacterial infections, basophils act as “first responders” and are also associated with modulation of the adaptive immune response. The maturation of pluripotent CD34⁺ stem cells into basophils is supported by the cytokine interleukin-3 (IL-3). The aim was to test the hypothesis that modulation of the adaptive immune response in bacterial infection by MGN-3/Biobran entails a basophilic response. The tick-related disorder Lyme borreliosis was chosen as the disease model; tick bites are associated with cutaneous IL-3-mediated basophil recruitment. Materials and Methods: A three-month randomised double-blind placebo-controlled trial was conducted in patients with a history of borreliosis who were suffering from symptoms attributable to this disorder. The immunoceutical group received oral Biobran; the dosage for both groups was 1 g thrice daily. Both groups were matched for age, sex, and ethnicity. Results: A higher percentage of basophil count occurred in the immunoceutical group (p = 0.038). The final general linear model included the group (immunoceutical/placebo) and change in fatigue assessed by the 11-item Chalder Fatigue Questionnaire (CFQ) (r² = 0.63; p = 0.0066). The change in basophil count was positively correlated with CFQ change (r_s = 0.633; p = 0.020); only the immunoceutical group showed a positive correlation. Conclusions: These results support the hypothesis being tested. Basophils may modulate the adaptive immune response by acting as immunoregulatory cells. They can regulate the functioning of type 2 T-helper lymphocytes, enhance immunological memory, and present antigens to CD8 T lymphocytes. Further studies are needed to clarify potential mechanistic factors and the timing of this basophilic response. Full article

The introduction of immune checkpoint inhibitors (ICIs) as a part of immunotherapy represented a therapeutic breakthrough in the landscape of cancer treatment. The action of these inhibitors consists of blocking certain inhibitory receptors in the immune system. Blocking these inhibitory pathways, ICIs induce an enhanced T cell-mediated response necessary to neutralize tumor cells. Over the last 10 years, programmed death cell protein1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been among the inhibitory receptors most targeted by ICIs. Currently, this innovative therapeutic approach faces two major challenges: early identification of cancer patients who are likely to get a significant therapeutic benefit through the use of these inhibitors, and the second challenge is the early prediction of likely immune-related adverse events (irAEs) associated with such therapy. The aim of the present text is to discuss the current research efforts to discover and develop much needed effective biomarkers, which may represent an important step towards more efficient and risk-free immunotherapy. We also highlight the increasing role in clinical analyses of liquid biopsy sampling combined with mass spectrometry-based proteomics and how such combination is contributing to current research efforts to enhance the role of immunotherapy. Full article

Diabetic atherosclerosis results from the interplay between metabolic dysfunction and immune dysregulation and remains the major cause of mortality in patients with diabetes mellitus (DM) worldwide. Emerging evidence indicates that impaired immune checkpoint signaling, particularly through the PD-1/PD-L1 and CTLA-4 pathways, contributes to the chronic vascular inflammation characteristic of diabetic cardiovascular disease. These checkpoints normally help maintain vascular homeostasis by limiting proatherogenic immune responses. In type 2 diabetes (T2D), which accounts for 90–95% of cases, chronic hyperglycemia downregulates checkpoint expression in both immune effector cells and the vascular endothelium. In type 1 diabetes (T1D), autoimmune-mediated checkpoint failure within the pancreatic islets extends to the vascular tissues, creating an early cardiovascular risk through overlapping but distinct mechanisms. The loss of checkpoint regulation amplifies Th1 and Th17 responses while impairing regulatory T cell function and accelerating plaque formation and destabilization. Observations from cancer patients receiving checkpoint inhibitors, who exhibit increased cardiovascular events, further highlight the importance of these pathways in vascular integrity. Restoring checkpoint signaling through targeted interventions, combined with biomarker-driven stratification and personalized immune profiling, may provide new strategies for preventing or slowing atherosclerotic progression in patients with diabetes. Full article

Immunotherapy has demonstrated significant efficacy in colorectal cancer (CRC), but its therapeutic effects remain limited in microsatellite stable (MSS) patients, indicating the critical role of the tumor immune microenvironment (TIME) in regulating immune responses. Lipid rafts, dynamic membrane microdomains enriched in cholesterol and sphingolipids, have emerged as potential targets for TIME remodeling through their integration of immune signal transduction, enrichment of cell death receptors, and regulation of immune cell functionality. This review outlines the pivotal mediating roles of lipid rafts in cellular survival, death, and tumor progression. Specifically, MSS-type CRC exhibits lipid raft structural remodeling driven by dysregulated lipid metabolism, which fosters multiple immune escape mechanisms through exosome-mediated immunosuppressive signaling, promotion of tumor-associated macrophage (TAM) M2 polarization, enhanced infiltration of regulatory T cells (Tregs), and functional exhaustion of effector cells, such as CD8⁺ T cells and NK cells. Finally, we discuss targeted therapeutic strategies based on lipid raft characteristics and CRC molecular profiles, proposing an innovative multidimensional treatment framework combining immune checkpoint inhibitors with lipid raft-targeted interventions and chemoradiotherapy. This approach provides theoretical and strategic support for overcoming CRC immunotherapy resistance and advancing clinical translation. Full article

Tissue-resident memory T (T_RM) cells persist long-term in non-lymphoid tissues and provide rapid local immune protection, yet emerging evidence shows they also act as key drivers of chronic inflammation and relapse in rheumatoid immune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and primary Sjögren’s syndrome (pSS). A systematic search of PubMed, Web of Science, and Google Scholar (through October 2025) identified studies on T_RM cell biology, pathogenic roles, and therapeutic modulation in autoimmune diseases. This review summarizes the fundamental features of T_RM cells, including their TGF-β and IL-15 dependent development, tissue-specific heterogeneity, and unique metabolic programs. It highlights disease-specific pathogenic mechanisms: promotion of osteoclastogenesis and chronic synovial inflammation via Granulocyte-macrophage colony stimulating factor (GM-CSF) and the IL-23/IL-17 axis in RA; amplification of type I interferon responses and autoantibody production in SLE; potential contribution to fibrosis through TGF-β secretion in SSc; and mediation of glandular injury through cytotoxicity in pSS. Therapeutic strategies targeting T_RM cells—such as JAK inhibitors, IL-17/IL-23 blockade, disruption of residency signals, metabolic interventions, and microenvironmental remodeling via nanotechnology—are critically evaluated. Challenges remain in achieving tissue-specific targeting without compromising systemic immune memory. Future directions include spatial transcriptomics, organoid models, and artificial intelligence to support precision medicine. Targeting T_RM cells presents a promising novel avenue for achieving long-term remission and potentially even a cure for rheumatoid immune diseases. Full article

Multiple myeloma (MM) is a clonal malignancy of terminally differentiated plasma cells characterized by bone marrow infiltration and excessive production of monoclonal immunoglobulins, leading to end-organ damage such as osteolytic bone lesions. Despite substantial therapeutic progress achieved with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, multiple myeloma remains incurable, and outcomes for triple-class-refractory patients remain dismal, with median survival below one year. Bispecific T cell engaging antibodies (TCEs) have recently emerged as a promising immunotherapeutic approach capable of redirecting cytotoxic T cells to eliminate malignant plasma cells. These engineered antibodies simultaneously engage CD3 on T cells and a tumor-associated antigen such as B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor homolog 5 (FcRH5), thereby forming an immune synapse that triggers T cell activation, cytokine secretion, and perforin–granzyme-mediated apoptosis of the targeted B cell. This review summarizes the molecular design, mechanism of action, and clinical development of TCEs in MM, encompassing early bi-specific T cell engagers (BiTE) constructs such as AMG 420 and next-generation IgG-like molecules including teclistamab. Pivotal clinical trials have demonstrated overall response rates between 43% and 73%, accompanied by durable remissions and manageable safety profiles. Future directions include earlier-line integration, synergistic combinations with immunomodulatory or costimulatory agents, and the development of trispecific formats to overcome antigen escape and T cell exhaustion. Collectively, TCEs represent a paradigm shift toward durable, immune-mediated disease control in multiple myeloma. Full article

Background: A major challenge in cancer treatment is the ability of tumor cells to adapt to immunotherapy through immune escape, often mediated by the PD-1/PD-L1 pathway. To investigate this, we adapted an ordinary differential equation model of combination therapy, incorporating the dynamics of the immune checkpoint inhibitor Avelumab and the immunostimulant NHS-muIL12. Methods: Using literature-derived parameter values, we refitted a single parameter across therapies, which showed that PD-L1 expression increased with immunotherapy, while Avelumab blocked its functional signaling, preventing PD-L1 from suppressing T-cell activity. Incorporating therapy-dependent, dynamically regulated PD-L1 expression enabled a biologically grounded mechanism to reproduce experimental observations, leading us to formulate PD-L1 tumor expression as a dynamic variable ($ϵ$) and providing a mechanistic basis for both therapeutic synergy and treatment failure. Results: We validated this mechanistic framework by showing that the distinct outcomes observed in two independent cancer datasets (EMT-6 and MC38) can be captured by the same model structure, differing only in the parameterization of tumor-specific parameters and PD-L1 regulatory dynamics. Our results indicate that tumor resistance is linked to dose-dependent upregulation of PD-L1 following NHS-muIL12 treatment, explaining treatment failure, while PD-1/PD-L1 blockade in combination therapy enables effective antitumor immune responses. Conclusions: This work provides a validated mechanistic framework for adaptive resistance in combination immunotherapy. Quantified parameter differences between responder and non-responder phenotypes enable clearer biological interpretation and support the development of predictive tools for optimizing treatment strategies. Full article

Enterovirus A71 (EV-A71) is a critical global pathogen, primarily causing Hand-Foot-and-Mouth Disease (HFMD) but frequently leading to severe neurological complications, including fatal neurogenic pulmonary edema (PE). This review elucidates the complex interplay between viral pathogenesis and the host immune response. EV-A71 utilizes receptors like SCARB2 and PSGL-1 for entry, while its proteases (2A^pro, 3C^pro) efficiently evade innate immunity by cleaving key signaling adaptors (MAVS, TRIF), suppressing Type I IFN response. Critical to disease progression is the age-dependent vulnerability in infants and the subsequent shift toward immunopathology. Severe disease is driven by a systemic cytokine storm and T cell dysregulation, characterized by a loss of control from Treg cells and a profound Th17/Treg imbalance, resulting in high levels of pathogenic cytokines (e.g., IL-17A, IFN-γ). Clinical progression is predicted by specific biomarkers, including Treg depletion, monocyte exhaustion (PD-1/PD-L1), and suppressed regulatory signaling (low cAMP). These findings highlight that effective therapeutic strategies must target host-mediated damage through immunomodulation (e.g., by exploring interventions against key pathogenic axes like IL-6 and IL-1β) and call for the development of next-generation vaccines capable of eliciting balanced cellular immunity to prevent immunopathology. Full article

Food allergies are rising globally, posing a multifactorial public health challenge driven by complex interactions among diet, immune development, and environmental exposures. This review highlights emerging insights into the cellular and molecular mechanisms by which specific dietary components, particularly vitamin A, fibre, indole compounds, and proteins, promote intestinal homeostasis. These nutrients act through both microbiota-dependent and -independent pathways, primarily in the small intestine, enhancing epithelial barrier integrity and supporting tolerogenic immune responses. Two key signalling axes, mediated by retinoic acid (RA) and aryl hydrocarbon receptor (AhR) ligands, converge to regulate RORγt-expressing immune cells, including group 3 innate lymphoid cells, TCRγδ⁺CD8αα⁺ intraepithelial lymphocytes (IELs), and Th17 cells, which are essential for secondary lymphoid organ development and barrier reinforcement. RA and AhR also guide the homing and specialization of diverse regulatory T cell subsets and CD4⁺ IELs, which collectively sustain peripheral tolerance to dietary antigens. Recent findings implicate RORγt⁺ antigen-presenting cells in the induction of peripheral Tregs during early life, particularly at weaning, underscoring a critical window for tolerance establishment. Microbial metabolites and commensal-derived signals further shape these immune pathways, reflecting the intricate interplay between host, diet, and microbiota in the regulation of oral tolerance. Full article