Search Results (612)

Chimeric antigen receptor (CAR)-engineered immune cell therapies have revolutionized cancer treatment, with CAR-T cells demonstrating remarkable efficacy against hematological malignancies. However, the effectiveness of CAR-T and other lymphocyte-based therapies against solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment and poor infiltration of effector cells. Recently, CAR-macrophage (CAR-M) immunotherapy has emerged as a promising strategy to overcome these barriers. Leveraging the innate tumor-homing ability, phagocytic function, and antigen-presenting capacity of macrophages, CAR-M therapies offer unique advantages for targeting solid tumors. This review provides a comprehensive overview of the development and current state of CAR-Macrophage immunotherapy, including advances in CAR design and macrophage engineering, preclinical and clinical progress, and mechanistic insights into their anti-tumor activity. The review critically examined both the benefits and limitations of CAR-M approaches, addressing persistent challenges such as cell sourcing, durability, and safety, while also exploring innovative strategies to enhance therapeutic efficacy. Finally, future perspectives and the potential clinical impact of CAR-macrophage therapies were outlined, underscoring their emerging role in the evolving landscape of cancer immunotherapy. Full article

During viral infection, NLR family CARD domain-containing protein 5 (NLRC5) participates in innate immunity through multiple mechanisms. These include regulating type I interferon and related immune factor expression, as well as modulating immune cell functions, such as cytotoxic T lymphocytes (CTLs) and macrophages, thereby promoting antiviral defence and maintaining immune homeostasis. Our study demonstrates that (1) Enterovirus 71 (EV71) infection upregulates NLRC5 expression through the RIG-I-IRF3-mediated IFN-β pathway, which in turn promotes MHC-I molecule expression and (2) NLRC5 suppresses EV71 replication and simultaneously restrains excessive inflammatory responses by fine-tuning IFN-β production through a negative feedback loop. This loop operates via two distinct mechanisms, namely, direct downregulation of key IFN-β pathway mediators (e.g., RIG-I and IRF3) and binding to the 5′UTR of the EV71 genome to inhibit viral replication, thereby indirectly dampening the IFN-β signal. Furthermore, we show that EV71 activates the NLRC5-dependent MHC-I response in an IFN-β-dependent manner. Collectively, these results elucidate the dual role of NLRC5 during EV71 infection, offering novel insights into viral pathogenesis and highlighting potential targets for antiviral drug development. Full article

Tumor tissue is surrounded by mast cells (MCs), which participate in the inflammatory immune response by producing cytokines, proteases, and other molecules. MCs are involved in both innate and acquired immunity and are associated with the IgE response through the FcεRI receptor. MCs mediate inflammation in several immune reactions, including acute hyperreactivity, leukocyte recruitment, acute tissue swelling, anaphylaxis, and pro-inflammatory cytokine production. They not only function as pro-inflammatory effector cells but may also contribute to the regulation of the acquired immune response in tumor tissue. Therefore, MCs may mediate immunity in breast cancer by promoting remodelling and counteracting cancer growth. They also produce anti-inflammatory substances, such as histamine, transforming growth factor-β (TGF-β)1, IL-10, and IL-4, which inhibit the acquired immune response and reduce the inflammatory state. IL-37 and IL-38 are novel natural regulators of inflammation and are anti-inflammatory members of the IL-1 family. IL-1, generated by immune cells such as macrophages and lymphocytes, is released downstream of oncogenes in breast cancer, triggering an inflammatory response by stimulating other pro-inflammatory cytokines such as IL-6, tumor necrosis factor (TNF), and IL-33 (an early warning cytokine). Therefore, blocking IL-1 with IL-37 or IL-38 could represent a novel therapeutic strategy that, when combined with other treatments, could be beneficial in breast cancer. This review focuses on the new discoveries and insights into the role of MCs in breast cancer. We also analyzed molecules that can promote tumor growth and those that can inhibit cancer development and metastasis. This review aims to study the role of MCs accumulated in the stroma of breast adenocarcinoma in relation to secreted anti-inflammatory cytokines, such as IL-37 and IL-38. Full article

Background and Objectives: Inflammation contributes to plaque rupture and thrombosis in ST-elevation myocardial infarction (STEMI). The Aggregate Index of Systemic Inflammation (AISI) is a novel biomarker that reflects innate immune and thrombotic activation. Due to the connection between inflammation and thrombosis, higher AISI values could indicate a greater thrombus burden and the necessity of glycoprotein IIb/IIIa inhibitors. The aim of this study was to assess the relationship between AISI and tirofiban use during primary percutaneous coronary intervention (PCI) in STEMI patients. Materials and Methods: This retrospective study included 2624 STEMI patients who underwent primary PCI at a tertiary heart center between 2019 and 2024. Patients with pre-hospital fibrinolysis, missing laboratory data, or rescue PCI were excluded. AISI was calculated as (neutrophil × monocyte × platelet)/lymphocyte. The primary outcome was tirofiban use during PCI. Univariate and multivariable logistic regression analyses were performed to identify independent predictors, and receiver operating characteristic (ROC) curve analysis was used to evaluate AISI performance. Statistical significance was defined as p < 0.05. Results: Among the 2624 patients with STEMI undergoing primary PCI, tirofiban was administered in 23.5% of cases. Patients receiving tirofiban had significantly higher AISI values (p < 0.001). ROC analysis demonstrated that AISI predicted tirofiban use with a modest discriminative performance (AUC = 0.566; 95% CI 0.536–0.596; p < 0.001). In multivariable logistic regression, younger age (OR 0.98; p < 0.001), higher AISI (per 100-unit increase; OR 1.01; p = 0.037), and lower LVEF (OR 0.98; p < 0.001) independently predicted tirofiban use, whereas admission glucose showed only borderline significance (p = 0.089). Conclusions: Elevated AISI was independently associated with tirofiban use during primary PCI, indicating that systemic inflammatory status parallels intraprocedural decision-making in STEMI. Although its discriminative performance was modest, AISI reflects systemic inflammatory–thrombotic activation in this clinical setting. Full article

Lidocaine, an amide-type regional anesthetic, has been an important medication in the field of anesthesia since its clinical approval. Recently, lidocaine has emerged as a powerful immunomodulatory agent beyond its classical anesthetic properties. This review has summarized the recent basic and clinical studies with sufficient evidence on the multifaceted effects of lidocaine on both innate and adaptive immune cells, including macrophages, neutrophils, eosinophils, basophils, natural killer (NK) cells, mast cells, dendritic cells (DCs), monocytes, and T lymphocytes. We have also detailed how lidocaine affects critical cellular processes, such as cellular polarization, cytokine production, phagocytosis, and apoptosis, through multiple signaling pathways, including NF-κB, TLR4/p38 MAPK, voltage-sensitive sodium channels, HIF1α, TGF-β/Smad3, AMPK-SOCS3, TBK1-IRF7, and G protein-coupled receptors. These immunoregulatory effects of lidocaine are dependent on its concentration, duration of action, and the microenvironment. The immunomodulatory actions of lidocaine may contribute to its potential therapeutic value in various settings of diseases, such as cancer, sepsis, acute lung injury, asthma, organ transplantation, ischemia–reperfusion injury (IRI), and diabetes. We propose that lidocaine can be repurposed as an immunomodulator for treating immune-mediated inflammatory diseases. However, future research should define optimal dosing strategies, validate its mechanisms of action in clinical trials, and explore its novel clinical applications as a complementary immunotherapy. Full article

The limited ability of the immune system to infiltrate solid tumors, attributed to the immunosuppressive tumor microenvironment (TME), remains a significant challenge in cancer therapy oncolytic adenovirus (OAd) that can directly kill tumor cells in addition to inducing both innate and adaptive immune responses. Therefore, the use of OAd to treat tumors is an appealing approach. In this study, we engineered an OAd armed with a human granulocyte–macrophage colony-stimulating factor (GM-CSF), controlled by the E2F promoter, Ad5/3-E2F-d24-GM-CSF (named OAd-Z1). The antitumor activity of OAd was tested in vitro and in vivo. These findings demonstrated that OAd expressed GM-CSF, replicated effectively in tumor cells, inhibited tumor growth, activated the de novo antitumor response, promoted apoptosis and immunogenic cell death in tumor cells, and increased cytokine and chemokine production both in vitro and in vivo. Additionally, OAd demonstrated an abscopal effect and stimulated T lymphocyte infiltration in vivo. Our findings demonstrate that OAd-Z1 represents promising immunotherapeutic candidates for lung cancer, with the potential to enhance systemic antitumor immunity. Full article

Rapid weight loss (RWL) is a common strategy among combat sports athletes aiming for a competitive advantage. However, it imposes significant immunological stress that compromises both innate and adaptive immune defenses. This systematic review synthesizes current experimental and mechanistic evidence on the effects of RWL in combat sports, focusing on cellular immunity, neuroendocrine regulation, and inflammatory pathways. Acute RWL activates the hypothalamic–pituitary–adrenal axis, elevating plasma cortisol and suppressing lymphocyte proliferation, T-cell function, and natural killer cell cytotoxicity. Although neutrophil counts increase, their phagocytic and oxidative burst capacities decline, reflecting impaired host defense. Monocyte and macrophage systems shift toward proinflammatory phenotypes, while mucosal immunity is weakened by reductions in secretory immunoglobulin A, leading to increased upper respiratory tract infection risk. The magnitude and speed of weight loss are critical determinants of immune dysfunction, with reductions exceeding 5% of body mass producing particularly severe consequences. Evidence-based intervention strategies—including gradual weight management, nutritional optimization, and biomarker monitoring—are essential to mitigate immunosuppression and safeguard athlete health. This review highlights key gaps in combat sports-specific protocols and proposes integrated approaches to preserve immune competence and optimize performance. Full article

Inflammation plays a pivotal role in the pathogenesis of acute coronary syndromes (ACS), contributing to plaque instability, thrombosis, and myocardial injury. This review aims to comprehensively examine the inflammatory mechanisms underlying ACS and evaluate current and emerging anti-inflammatory therapeutic strategies. We conducted a comprehensive literature review examining the role of inflammatory pathways in ACS pathophysiology, including innate and adaptive immune responses, key inflammatory mediators, and cellular mechanisms. We analyzed current evidence for anti-inflammatory therapies and their clinical outcomes in ACS management. Inflammatory processes in ACS involve complex interactions between innate immune cells (neutrophils, macrophages, monocytes) and adaptive immune cells (T lymphocytes, B cells). Key mechanisms include neutrophil extracellular trap (NET) formation, macrophage polarization, T cell subset imbalances (Th1/Th17 predominance with regulatory T cell dysfunction), and complement activation. Inflammatory biomarkers such as C-reactive protein, interleukin-6, and NET-specific markers demonstrate prognostic value. Anti-inflammatory therapies including colchicine, canakinumab (IL-1β inhibition), and methotrexate have shown cardiovascular benefits in clinical trials. Emerging targets include NET inhibition, T cell modulation, and precision inflammatory profiling approaches. Inflammation represents a critical therapeutic target in ACS beyond traditional risk factor modification. While colchicine and IL-1β inhibition have demonstrated clinical efficacy, future strategies should focus on precision medicine approaches targeting specific inflammatory pathways based on individual patient profiles. Integration of anti-inflammatory therapy with lipid management and antithrombotic strategies offers promise for improving ACS outcomes through comprehensive targeting of the multifactorial pathophysiology underlying coronary artery disease. Full article

Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes in the human liver which can provide antimicrobial defense, amplify inflammatory processes and mediate tissue repair and fibrosis depending on microenvironmental cues. Chronic liver diseases of diverse etiologies, including viral hepatitis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, biliary tract disease, autoimmune hepatitis and hepatocellular carcinoma are accompanied by numerical and functional adjustments in the MAIT cell population. In this review, we integrate existing data on MAIT cell markers and functions in diverse liver diseases, comparing how these cells are similarly or differentially shaped by distinct pathogenic contexts. Finally, we propose a spatially anchored conceptual and technical framework to study MAIT cell biology in liver disease. Full article

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease characterized by the destruction of pancreatic β-cells. Both lymphocytes and various innate immune cells contribute to its immunopathogenesis. Among lymphocytes, in addition to CD8⁺ T cells, CD4⁺ T cells, and B cells, growing attention has been directed toward some unconventional T-cell subsets, such as TCRαβ⁺ double-negative T (DNT) cells, based on findings in several autoimmune/rheumatic diseases. This narrative review aims to summarize and analyze the available data on the potential role of DNT cells (and, in detail, the TCRαβ⁺ subset) in the immunopathogenesis of autoimmune diabetes/T1DM. Most of the current knowledge regarding DNT cell homeostasis in this pathological setting derives from experimental models, especially Non-Obese Diabetic (NOD) mice. In murine autoimmune diabetes, TCRαβ⁺DNT cells appear to exert a predominantly protective role against immune-mediated β-cell injury. These cells can be observed in multiple anatomical sites, including the thymus, peripheral blood, secondary lymphoid organs (spleen and lymph nodes) and, under pathological conditions, in non-lymphoid organs, like within the pancreas and, in detail, pancreatic islets, in the setting of autoimmune diabetes. Experimental evidence suggests that TCRαβ⁺DNT cells may attenuate the CD8⁺ T cell-mediated destruction of pancreatic β-cells, both directly and indirectly, through the inhibition of CD4⁺ T cells and B cells implicated in this immunopathological process. Unfortunately, very few studies have examined TCRαβ⁺DNT cells in patients with T1DM. This important knowledge gap highlights the need for dedicated clinical and translational research to better elucidate the role of TCRαβ⁺DNT cells in T1DM, especially given the preliminary findings pointing toward their potential immunoregulatory relevance. Full article

This experiment was designed to systematically evaluate the immunomodulatory effect of water extract of Artemisia annua L. (WEAA) on sheep, both in vivo and in vitro, and to determine the involvement of the TLR4/NF-κB signaling pathway in mediating these effects. In experiment 1, 32 female sheep (Dorper × Han, 3 months old, 24 ± 0.09 kg each) were designated to 4 groups, with each group receiving a basal diet supplemented with, respectively, 0 (control group), 500, 1000, and 1500 mg/kg WEAA. The serum, liver, and spleen immune indicators and related gene expressions were measured. In experiment 2, the peripheral blood lymphocytes (PBLs) were processed with WEAA (0, 25, 50, 100, 200, and 400 μg/mL), with six replicates assigned to each concentration group, then the cell viability, immune function, and related gene expressions were measured, and the optimal concentration of WEAA was determined. In experiment 3, the experimental groups consisted of PBLs subjected to treatments with or without PDTC (NF-κB inhibitor) and with or without WEAA, forming four distinct treatment groups (six replicates/group): PDTC(−)/WEAA(−) group, PDTC(−)/WEAA(+) group, PDTC(+)/WEAA(−) group and PDTC(+)/WEAA(+) group. The immune indexes and TLR4/NFκB pathway related indexes were determined. The results were as follows: WEAA dose-dependently enhanced the content of immunoglobulins (IgA, IgG, IgM) and cytokines (IL-1β, IL-2, IL-4) in the serum, liver, and spleen tissues, among which IgA, IgG, and IL-4 were the most significantly affected core indicators (p < 0.05). Meanwhile, WEAA dose-dependently upregulated the expression of TLR4/NF-κB pathway-related genes (TLR4, IKKβ, IκBα, NF-κBp65) and their downstream cytokine-related genes (IL-1β, IL-4) in liver and spleen tissues (p < 0.05). Of these genes, liver IL-4, IκBα, and spleen IL-4 were the most prominently regulated core genes (p < 0.05), The optimal supplementary dose of WEAA was determined to be 1000 mg/kg. In addition, adding 100 μg/mL WEAA to the culture medium of PBLs significantly enhanced immune function and cell viability. The underlying mechanism involved the TLR4/NF-κB pathway; that is to say, WEAA enhanced sheep’s immune indicators by upregulating TLR4/NF-κB pathway genes, thereby coordinately regulating humoral and innate immunity, thereby improving the immune indices of sheep. This study provided compelling experimental support for the prospective utilization of WEAA as a functional feed supplement in intensive meat-type sheep production systems. Full article

While the distinct roles of lymphocyte populations are well characterized in adaptive immunity, the phenotypic and functional diversity of innate immune cells is less explored. In recent years, subsets of monocytes have gained attention, as prominent shifts in population frequencies have been observed in disease states such as cancer. This narrative review summarizes current knowledge of the distribution and functional differences among the three major monocyte subsets (classical, intermediate, non-classical) in tumor settings. It includes rare populations, such as neutrophil-like, CD56+, and Tie2-expressing monocytes. Scientific evidence indicates that the phenotypical and functional heterogeneity of monocyte subsets determines their roles in either preventing cancer development or supporting the progression of disease through a remarkable diversity of mechanisms. Of note, alterations in the distribution of monocyte subsets and their functional reprogramming have been identified as drivers of cancer progression. While changes in monocyte frequencies have limited diagnostic biomarker potential for cancer detection, they may reflect the progression of disease and response to therapy. Based on subset-specific properties, distinct monocyte populations are increasingly recognized as promising targets of cancer immunotherapy. Yet novel strategies targeting monocyte populations must consider the risk of treatment reversal given the high plasticity of these cells. Full article

Research Subject: Primary and secondary immunodeficiencies represent a growing clinical and public health challenge due to increased susceptibility to infections, impaired immune regulation, chronic inflammation, and disturbances in redox homeostasis. The pathophysiology of these disorders involves dysfunction of innate and adaptive immunity, altered cytokine production, oxidative stress, and reduced activity of antioxidant defense mechanisms. In recent years, attention has increasingly focused on the role of oxidative imbalance and chronic inflammation in weakening immune function. Ozone therapy, when used at controlled low doses, induces a hormetic response that triggers adaptive antioxidant pathways, modulates cytokine profiles, and enhances the activity of immune cells. Due to these properties, ozone has emerged as a potential adjunctive therapy aimed at restoring immune homeostasis and improving clinical outcomes in patients with immune disorders. Aim of Study: The aim of this review is to discuss the role of oxidative stress and immune dysregulation in the pathogenesis of immunodeficiencies and to provide an updated overview of current evidence regarding the therapeutic potential of ozone therapy. This article summarizes molecular mechanisms, biochemical effects, and clinical findings related to ozone-based interventions, with particular emphasis on cytokine modulation, redox balance, macrophage function, regulatory T cells (Treg), and NK cell activity. Materials and Methods: This review is based on scientific data retrieved from PubMed, Scopus, and Google Scholar. Included sources comprise randomized clinical trials, observational studies, meta-analyses, mechanistic studies, and review articles published between 1996 and 2025. Keywords used during the literature search included: “ozone therapy”, “immunomodulation”, “oxidative stress”, “inborn errors of immunity”, “secondary immunodeficiency”, “Treg cells”, “redox homeostasis”. Results: Analysis of current studies shows that controlled low-dose ozone (typically 10–40 µg/mL) activates the Nrf2/ARE antioxidant pathway, increases enzymatic defense (SOD, catalase, GPx), and reduces levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. Clinical trials report improved lymphocyte profiles, enhanced macrophage phagocytic function, increased Treg activity, and reinforced NK cell responses. Patients receiving ozone therapy demonstrate reductions in inflammatory markers (CRP, IL-6, D-dimer), improved redox balance, decreased infection frequency, and better overall immune performance. The therapy is generally well tolerated when administered within established safety guidelines. Conclusions: Available evidence indicates that ozone therapy may serve as a valuable adjunct in the management of immunodeficiencies by modulating immune responses, reducing oxidative stress, and restoring homeostatic balance. Although current clinical outcomes are promising, further multicenter randomized trials are needed to standardize dosing protocols, assess long-term effectiveness, and confirm safety. Full article

Peripheral blood serves both as a source of effector immune cells that migrate to exocrine glands and as a reflection of the immunological changes occurring in patients with Sjögren’s disease (SjD). These changes may be linked to the clinical state of these patients. We analyzed total cell counts in the peripheral blood, as well as frequencies of individual leukocyte subpopulations, membrane expression levels of CD38 and CD157, and serum concentrations of soluble sCD38 and sCD157 in SjD patients (n = 40) and age-matched healthy controls (n = 20). Hierarchical clustering based on the cell count of leukocyte subpopulations was employed to identify distinct patient subgroups. Associations between these clusters and clinical parameters were subsequently evaluated. Key findings included a reduction in lymphocyte counts and their subpopulations, alongside increased CD38 expression on CD38⁺ B cells (p = 0.047) and, unexpectedly, on monocytes (p = 0.014) when comparing patients and controls. The involvement of innate immunity was further supported by the differential expression of CD157 across patient samples. Patients with low cell counts exhibited reduced CD157 expression on monocytes and granulocytes (p < 0.02), tested positive for anti-Ro antibodies, and reported severe fatigue. Our findings suggest that innate immune cells, such as monocytes and granulocytes in peripheral blood, are also likely to contribute to the manifestation and progression of SjD. The differential expression of CD157 may reflect distinct immunopathological states and warrants further investigation, as its precise role in exocrine gland involvement and extra-glandular manifestations lies beyond the scope of this study. Full article

Background: Vitamin D is increasingly recognized as a key immunomodulatory nutrient, influencing innate and adaptive immune responses. While 25-hydroxyvitamin D [25(OH)D] is widely used to assess vitamin D status, the active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D], may exert distinct effects on immune function. This study investigates the concentration-dependent and sex-specific relationships of both vitamin D metabolites with systemic inflammatory markers in a large clinical cohort. Objectives: To characterize the associations of 25(OH)D and 1,25(OH)₂D with total white blood cell (WBC) count and leukocyte subtypes, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Methods: We conducted a retrospective cross-sectional analysis of 125,537 adults (37.9% male; age 18–89 years) from routine laboratory diagnostics collected between 2014 and 2020 in Germany. Serum 25(OH)D and 1,25(OH)₂D were measured using standardized chemiluminescent immunoassays. Inflammatory markers were assessed via automated hematology. Multivariable-adjusted linear and non-linear regression models were used to assess associations, adjusting for age, sex, and season. Results: Neutrophils and Monocytes: Displayed U-shaped associations with both 25(OH)D and 1,25(OH)₂D. Neutrophil counts were lowest at 25(OH)D levels of ~40–60 nmol/L and increased significantly at both lower and higher extremes (p < 0.001). Lymphocytes: Inverse relationship with 25(OH)D (p < 0.001), and an inverse U-shaped relationship with 1,25(OH)₂D, peaking at ~90 pmol/L, with counts decreasing at both lower and higher levels (p < 0.001). Sex-specific analysis revealed that the relationship between 1,25(OH)₂D and lymphocyte count remained independent only in men, Eosinophils and Basophils: Demonstrated consistently negative correlations with both forms of vitamin D across all concentration ranges (p < 0.001). Conclusions: Our findings reveal distinct, concentration-dependent associations between vitamin D metabolites and leukocyte profiles, with evidence for nonlinear and sex-specific immunological effects. Both low and high levels of 25(OH)D and 1,25(OH)₂D were linked to increased neutrophil and monocyte counts, suggesting that vitamin D excess, like deficiency, may be linked to low-grade inflammation. These data are hypothesis-generating and suggest that personalized monitoring of vitamin D status may be relevant for future research on immune health, particularly in populations at risk for inflammatory or metabolic disease, but they do not provide a basis for clinical decision-making. Full article