The tumor microenvironment (TME) is a complex ecosystem where mechanical forces are now recognized not as passive byproducts but as active drivers critically shaping anti-tumor immunity. This review introduces the integrative concept of the "Mechano-immunological Landscape" (MIL) to delineate the dynamic and spatially heterogeneous network of interactions between mechanical cues and immune cells within tumors. We systematically elaborate on its three core pillars: Mechano-immunological Checkpoints, Mechano-immune Memory, and Landscape Plasticity. Building upon this framework, we propose a novel therapeutic paradigm termed "Mechano-immunological Landscape Remodeling Therapy" (MILRT). This paradigm discusses potential strategies to reverse immune suppression and enhance anti-tumor efficacy by modulating the mechanical TME, including matrix de-stiffening, mechanical empowerment of immune cells, and targeting mechano-immunological checkpoints. Finally, we outline future research trajectories, pivotal challenges, and clinical translation prospects in this burgeoning field. We position MILRT as a multi-pronged and synergistic framework that leverages advanced biomaterials and biophysical tools to overcome current limitations in drug delivery and immunotherapy resistance, thereby paving the way for next-generation, mechano-aware immunotherapies and redefining the future of solid tumor treatment.
Inflammatory bowel disease (IBD) is characterized by a refractory, relapsing inflammatory state driven by a multifaceted and poorly understood interplay between host mucosal metabolic disturbances and immune microenvironment dysregulation. To uncover robust non-invasive diagnostic indicators, this study implemented an integrated analytical framework combining advanced machine learning feature selection, penalized logistic regression modeling, and leave-one-dataset-out cross-validation to construct a novel diagnostic signature derived from metabolic cell death-related genes (MCDRGs). Systematic multiple-testing correction and rigorous data harmonization were applied across all independent discovery and validation cohorts to control for potential batch effects. Through this approach, we successfully identified a core three-gene candidate panel comprising indoleamine 2,3-dioxygenase 1 (IDO1), lipocalin 2 (LCN2), and solute carrier family 6 member 14 (SLC6A14). Methodologically, we demonstrated that the initial near-perfect apparent discrimination within the discovery cohort was mathematically attributable to quasi-complete data separation rather than systemic model overfitting. This identified signature exhibited consistent cross-cohort validation and correlated tightly with the coordinated infiltration and functional states of multiple mucosal immune cell subsets. Furthermore, independent clinical assays substantiated the synchronized elevation of these markers during active clinical phases, while orthogonal single-cell RNA-sequencing confirmed their prominent, cell-type-specific enrichment within the myeloid, epithelial, and stromal compartments of inflamed intestinal mucosa. Collectively, the identified MCDRGs, IDO1, LCN2, and SLC6A14, link metabolic dysregulation, immune infiltration, and regulated cell death, offering insights into IBD pathophysiology and providing a transcriptomic candidate signature with exploratory diagnostic potential for IBD stratification.
Inflammation in the female genital tract (FGT) is a key risk factor for HIV acquisition, but it remains unclear whether clinical or immunological measures best predict risk. We aimed to prospectively compare HIV acquisition among women with clinically and/or immunologically defined inflammation. HIV-uninfected women enrolled in the CAPRISA 004 tenofovir gel randomized controlled trial in South Africa were followed for up to 34 months. We analyzed data from 889 women, with cytokine measurements available for 774 participants. Clinical genital abnormalities were assessed at scheduled visits, and 48 cytokines were measured in cervicovaginal lavage samples. HIV incidence was compared across categories of clinical and immunological inflammation using time varying Cox proportional hazards models, adjusting for relevant covariates. Immunological inflammation, defined as ≥9 elevated cytokines, was present in 18% (140/774) of women. Among specific clinical signs, abnormal genital discharge (aHR: 2.67, 95% CI: 1.14-6.23, p=0.024) and cervicitis (aHR: 10.34, 95% CI: 2.46-43.65, p=0.001) were significantly associated with increased HIV acquisition. Women with both clinical and immunological inflammation had the highest risk of HIV acquisition, with adjusted hazard ratios of 2.08 (95% CI: 1.10-3.91, p=0.022) and 2.46 (95% CI: 1.21-5.03, p=0.013), respectively. Clinical and immunological definitions of inflammation were each independently associated with increased HIV acquisition risk and combined they reflected greater susceptibility. These findings highlight the important role of genital inflammation in women's HIV susceptibility, suggesting that clinical signs may provide practical early indicators of risk even as cytokine profiles provide a more sensitive measure of underlying inflammation.
Type 1 diabetes (T1D) exhibits age-related heterogeneity in clinical progression and immune pathology, yet the underlying molecular mechanisms remain poorly understood. Here, we integrate microbiome, metabolome, lipidome, and transcriptome profiling from 108 newly diagnosed pediatric patients with T1D, along with 56 healthy controls, to investigate age-related endotypes. Patients were stratified into early-onset (E-T1D, <7 years), intermediate-onset (I-T1D, 7-12 years), and late-onset (L-T1D, ≥13 years) groups. Multi-omics analyses revealed distinct molecular signatures among T1D subgroups. The most enriched microbial signatures were the genus Acetatifactor in E-T1D, the phylum Firmicutes A in I-T1D, and the family Bacteroidaceae in L-T1D (Linear Discriminant Analysis scores = 3.49, 5.56, and 5.78, respectively). For metabolites, pipecolic acid increased most in E-T1D, testosterone in I-T1D, while N-acetylhomocitrulline was most enriched in L-T1D. Lipidomic profiling revealed subgroup-specific alterations, with increased levels of LPA(16:1) in E-T1D, TG(16:0/18:2/18:3) in I-T1D, and TG(18:0/18:1/18:1) in L-T1D. The proportion of peripheral B cells to total lymphocytes was the highest in E-T1D (median = 11.64%) and associated with upregulated immune-related pathways, lowest in L-T1D (median = 5.99%) and linked to metabolic processes, while I-T1D (median = 8.47%) exhibited intermediate features of both groups. Integration of multi-omics interaction networks and experimental validation revealed that the microbial species Dialister invisus may promote peripheral B cell proliferation via docosapentaenoic acid, potentially contributing to early-onset T1D. Together, these findings provide a molecular framework for understanding age-related T1D endotypes and suggest potential targets for precision intervention. Workflow and key findings of the study.A multi-omics integration strategy was applied to newly diagnosed pediatric type 1 diabetes (T1D) patients stratified by age at diagnosis: early-onset (E-T1D), intermediate-onset (I-T1D), and late-onset (L-T1D), to delineate age-related T1D endotypes. Comprehensive profiling included gut microbiome, serum metabolome, lipidome, and peripheral immune transcriptome analyses. An integrated multi-omics interaction network revealed 665 direct microbiota-gene connections and 2,608 microbiota-metabolite/lipid-gene triadic interactions, highlighting a D. invisus-docosapentaenoic acid (DPA)-STMN1 axis mediating B-cell activation in early-onset T1D.
Boron neutron capture therapy (BNCT) is a targeted radiotherapeutic modality that employs boron-10 (10B) to capture thermal neutrons, thereby releasing high-linear energy transfer α-particles and lithium ions that selectively eradicate tumor cells while sparing the surrounding normal tissues. Immune checkpoint inhibitors (ICIs), including inhibitors of PD-1/PD-L1 and CTLA-4, enhance antitumor immunity by alleviating immunosuppression within the tumor microenvironment. As immunotherapy continues to expand across multiple tumor types and becomes integral to systemic cancer treatment, attention has increasingly focused on combining systemic immunomodulation with localized therapies. BNCT functions primarily as a local therapeutic approach, whereas ICIs elicit systemic immune activation. Whether the two modalities can produce synergistic therapeutic effects remains an important question.In this narrative review, we summarize current mechanistic insights, preclinical and clinical developments, and ongoing challenges associated with the combination of BNCT and ICIs, highlighting the potential of this strategy to achieve durable, synergistic antitumor responses.
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The resistance to apoptosis and immune evasion of tumor cells significantly increase the risk of cancer treatment failure. Ferroptosis has emerged as a new strategy to address apoptosis resistance in tumor therapy. However, traditional ferroptosis inducers often lead to drug resistance due to the compensatory mechanism of GPX4, while the synergistic effect of photothermal-immunotherapy can circumvent this limitation. Additionally, relying solely on innate immunotherapy may fail to effectively suppress aggressive tumors with "cold" and immunosuppressive microenvironments, thereby inducing immune escape. Here, we have meticulously developed a mild photothermal immunotherapy nanoplatform (termed Fe-Mn@GOx NPs), designed to induce non-apoptotic ferroptosis, augment cGAS-STING pathway activation and enhance innate anti-tumor immunity. This strategy directly disrupts the structure of heat shock protein (HSP) to restore the sensitivity of cancer cells and enhance antitumor immunity. Notably, Fe-Mn@GOx NPs-mediated ferroptosis induces an elevation in reactive oxygen species (ROS) levels within tumor cells. Additionally, glucose depletion itself primarily affects ATP levels. ROS-mediated oxidative damage, combined with ATP depletion-induced functional inhibition, synergistically inhibits heat shock protein (HSP) expression, thereby offering a potent approach for mild photothermal immunotherapy. More critically, the cGAS-STING pathway in macrophages is further activated by tumor-derived endogenous DNA contained within Fe-Mn@GOx NPs-induced dead cell debris, simultaneously promoting the generation of long-term immune memory T cells. The interplay between ferroptosis and the cGAS-STING pathway triggers rapid induction of systemic antitumor immunity, leading to suppression of tumor growth. The engineered nanotherapeutic platform enables a novel tumor immunotherapy strategy through specific cGAS-STING pathway activation.
Tumour-draining lymph nodes (TDLNs) serve as the closest immunological hubs to the primary tumour site in colorectal cancer (CRC). Owing to their unique and irreplaceable anatomical advantage and dynamic immune cell repertoire, TDLNs represent an intensively studied immunological niche and are a potential therapeutic target. This study aimed to map the immune microenvironment of CRC TDLNs to identify targetable immunomodulatory axes. Single-cell RNA sequencing (scRNA-seq) was performed on 23 quadruplet-matched samples, including primary tumours, adjacent normal tissues, tumour-free lymph nodes (TFLN) and tumour-invaded lymph nodes (TILN) from seven CRC patients. Mechanistically significant findings were further validated through in vitro functional assays, CRISPR knockout in primary regulatory T cells (Tregs), in vivo murine footpad-popliteal lymph node metastasis models with lipid nanoparticle-encapsulated siSPP1 (LNP-siSPP1) and/or anti-CD44 mAb, and multiomics analysis of independent CRC cohorts. scRNA-seq analysis delineated TILN-specific immunological landscapes dominated by SPP1+ macrophage expansion and active Treg differentiation niches, establishing TILNs as maturation hubs for Tregs versus TFLNs. Mechanistically, SPP1+ macrophages drove Treg differentiation into immunosuppressive CD137+ subsets via the SPP1-CD44 axis, which required NF-κB1 to directly bind the TNFRSF9 promoter. In vivo, LNP-siSPP1 plus anti-CD44 mAb synergistically suppressed lymph node metastasis, reduced CD137+ Tregs and enhanced CD8+ T cell function. Findings were consistently observed across all experimental models and patient-derived datasets. SPP1+ macrophages established an immunosuppressive niche in CRC TDLNs by promoting CD137+ Treg maturation via the SPP1-CD44-NF-κB1 axis. Targeting this axis with LNP-siSPP1 and anti-CD44 mAb might overcome Treg-mediated immunosuppression in CRC.
Psoriasis is an immune-mediated inflammatory skin disease with variable biologic therapy response. Current treatment selection lacks reliable predictive biomarkers for personalized decisions. To identify distinct immunological patient subgroups based on peripheral blood immune cells and evaluate their association with biologic therapy efficacy. This retrospective cohort study included 329 plaque psoriasis patients initiating first-time biologic therapy and 169 healthy controls. Peripheral blood flow cytometry data were analyzed using hierarchical clustering. Kaplan-Meier analysis assessed time to PASI90 achievement among subgroups. Psoriasis patients showed significantly elevated lymphocyte populations. Three distinct immunological clusters were identified: Cluster 1 (57.8%) with moderate T cells and low NK cells; Cluster 2 (27.7%) with decreased T cells and increased NK cells; and Cluster 3 (14.6%) with increased total lymphocytes. Cluster 1 patients achieved PASI90 significantly faster with both IL-17 and IL-23 inhibitors (p < 0.001). Peripheral blood flow cytometry identified distinct psoriasis immunophenotypes with significant differences in biologic therapy response, offering potential biomarkers for treatment selection and personalized medicine approaches.
Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we profiled the role of Colony-Stimulating Factor 1 Receptor (CSF1R) in cancer. We specifically focused on pancreatic ductal adenocarcinoma (PAAD), analysing its regulative function in cancer progression and its usefulness as a potential biomarker and therapeutic target. Using the TCGA and GEO databases, gene expression, survival prognosis, genetic abnormalities, immune infiltration, and CSF1R-related gene enrichment related to the CSF1R gene in patients with PAAD were studied. CSF1R expression appears to affect the development of PAAD; there is more CSF1R expression in the tumour tissue than in nearby normal tissues. There was no statistical difference in the overall survival or diseasefree survival of CSF1R expression. Analysis of changes in the CSF1R gene showed that PAAD samples had a low mutation frequency, and CSF1R gene amplification was the main reason. It was additionally emphasized that the impact of CSF1R on the tumor microenvironment, as evidenced by an immunological infiltration analysis, showed a strong correlation between the estimated infiltration values of cancer-associated fibroblasts and CSF1R expression in PAAD. This additional evidence was found for CSF1R expression in cancer-associated fibroblasts in PAAD. Targeting CSF1R might be a promising strategy for PAAD treatment. Inhibiting CSF1R activity or TGF-β binding to CSF1R inhibits tumour growth and immune escape. Investigating the link between CSF1R, TGF-β, and the immune system leads to new opportunities for combination therapies that integrate targeted medicine with immunotherapy. Targeting CSF1R might be a PAAD treatment. Inhibiting CSF1R activity or TGF-β binding to CSF1R inhibits tumour growth and immune escape. Investigating the link between CSF1R, TGF-β, and the immune system opens new opportunities for combining targeted medicines with immunotherapy.
Acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) are both cerebrovascular accidents where clinical management remains predominantly symptomatic, with few immunologically-targeted approaches. This cross-sectional study compared AIS (n = 73), ICH (n = 28), and controls (n = 31) in terms of demographic, clinical, laboratory, and immunological parameters, including regulatory T cells (Tregs), effector regulatory T cells (eTregs), CD4+ T cells, and cytokines. ICH patients showed lower total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) than both controls and AIS patients, whereas AIS patients had reduced high-density lipoprotein cholesterol (HDL-C) versus controls. Both stroke groups exhibited higher proportions of Tregs and eTregs versus controls. Correlation analyses revealed divergent immune networks: in AIS, the percentages of Tregs and eTregs positively correlated with interleukin-10 (IL-10), interleukin-1β (IL-1β), and interleukin-2 receptor (IL-2R), whereas in ICH, these percentages negatively correlated with tumor necrosis factor-α (TNF-α). We conclude that AIS features 'compensatory immune regulation', while ICH is characterized by 'uncontrolled innate immune inflammation', indicating two distinct immunological diseases with implications for subtype-specific therapy.
Induction immunosuppression in kidney transplantation requires a longitudinal perspective that extends beyond early rejection prevention to encompass long-term graft durability and patient safety. In response to the recent propensity score-matched study by Chukwu et al, complementary considerations are provided that address two underrecognized dimensions: Cumulative immunological burden and the downstream interaction between induction strategies and maintenance immunosuppression. Potent lymphocyte-depleting agents, despite comparable short-term rejection rates, are associated with a disproportionate "immunological debt" in standard-risk recipients, manifested by increased viral complications, malignancy, impaired graft function, and inferior death-censored graft survival. In contrast, non-lymphocyte-depleting induction preserves immune competence while maintaining adequate rejection control in this population. The integration of strict risk stratification, extended surveillance protocols, and dynamic reassessment of maintenance immunosuppression into standardized induction pathways is essential to optimize long-term outcomes. Framing induction therapy as a long-term commitment rather than a perioperative intervention supports alignment of immunosuppressive intensity with recipient risk and sustained graft stewardship.
Psoriatic arthritis (PsA) often requires escalation from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to biologic therapy (bDMARDs), yet biomarkers guiding treatment decisions remain limited. Anti-CD74 autoantibodies have shown diagnostic potential in axial spondyloarthritis, but their relevance in PsA is insufficiently characterized. To evaluate whether IgA anti-CD74 levels are associated with treatment escalation in peripheral PsA (pPsA) and to characterize their relationships with clinical and immunological parameters. Serum samples from 171 PsA (127 pPsA, 44 axial PsA [axPsA]), 43 non-rheumatic disease controls (NRD), and 43 rheumatoid arthritis (RA) patients were analyzed. IgA anti-CD74 levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were stratified by disease duration and treatment exposure. Correlation analyses, receiver operating characteristic (ROC) curves, and logistic regression models were performed. A prospective subgroup of 53 early pPsA patients was followed to assess treatment initiation. IgA anti-CD74 levels were elevated in PsA compared with NRD controls (median 13 vs. 6 U/mL, p < 0.0001), with similar levels in pPsA and axPsA and comparable values in RA, indicating an association with inflammatory disease rather than disease specificity. Anti-CD74 positivity (>15 U/mL) was observed in 31.5% of pPsA and 43.2% of axPsA versus 2.3% of NRD, independent of disease duration. Anti-CD74 levels were associated with treatment escalation in pPsA, with higher levels in bDMARD-treated patients (median 13.0 vs. 11.0 U/mL, p = 0.04). In multivariate analyses, anti-CD74 was independently associated with csDMARD (OR 1.113, p = 0.022) and bDMARD use (OR 1.052, p = 0.02). After false discovery rate (FDR) correction, anti-CD74 remained associated with serum IgA (q = 0.0008) and weakly with IgG (q = 0.0250), but not with C-reactive protein (CRP) or age. Longitudinal associations were not significant after FDR correction (csDMARD initiation: p = 0.047, q = 0.094; bDMARD initiation: p = 0.19, q = 0.1866), indicating these findings are exploratory. IgA anti-CD74 levels are elevated in PsA and appear to reflect immunological activity not captured by CRP. Their independent association with treatment escalation in pPsA supports further evaluation as a biomarker candidate, although findings remain exploratory and require validation in larger longitudinal cohorts.
Autologous tumor vaccines have been investigated as immunotherapeutic strategies in veterinary oncology and may represent relevant translational models for comparative cancer immunotherapy. However, reported clinical outcomes in dogs remain heterogeneous. To evaluate the safety, clinical outcomes, and immunological assessment methods of autologous tumor vaccines in dogs. A systematic review of PubMed, Web of Science, and Scopus identified 24 eligible studies evaluating autologous tumor vaccines in dogs. Vaccine platforms, safety data, clinical outcomes, and immunological assessments were analyzed descriptively. Exploratory pooled hazard ratio analyses were performed using random-effects models when applicable. Autologous tumor vaccines were generally reported as well tolerated, with predominantly mild and transient adverse events. Clinical outcomes varied substantially across tumor types and study designs. Canine lymphoma represented the setting with the greatest concentration of evidence, including the few randomized and controlled studies identified. Several lymphoma studies reported longer time to progression and lymphoma-specific survival in vaccinated dogs compared with chemotherapy-alone or historical comparator groups, although findings were not consistent across all studies. Exploratory pooled analyses suggested a trend toward reduced risk of progression and lymphoma-related mortality in immunotherapy-treated dogs; however, these findings should be interpreted cautiously given the limited number of studies and methodological heterogeneity. In solid tumors, outcomes were more variable and evidence remained predominantly exploratory. Current evidence suggests that autologous tumor vaccines in dogs are generally feasible and well tolerated, although methodological limitations restrict interpretation of therapeutic efficacy. Further prospective and standardized studies are needed to clarify their role in veterinary oncology and comparative cancer immunotherapy.
To assess clinical and immunological characteristics, disease activity, and lymphoma development in a well-characterized cohort of patients with Sjögren's disease, with particular emphasis on differences between glandular and systemic phenotypes. We conducted a retrospective observational study of adult patients (≥18 years) with Sjögren's disease not associated with any other systemic autoimmune rheumatic disease, defined as primary Sjögren's disease (pSjD), who were seen at a tertiary center in Madrid, Spain. Patients were classified according to the 2016 ACR/EULAR criteria or, alternatively, according to a modified version in which salivary gland ultrasonography (SGUS) was used as an alternative minor criterion when unstimulated whole salivary flow (UWS) and/or ocular staining score (OSS) were not available. For patients diagnosed before 2016, clinical data from medical records were used to apply these criteria retrospectively during the study period. SGUS findings were graded according to the Outcome Measures in Rheumatology (OMERACT) scoring system or based on expert radiologists' assessment. Systemic disease activity was assessed using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Demographic, clinical, laboratory, histopathological, lymphoma occurrence, and treatment data were retrospectively collected. Patients were stratified into glandular (exocrine-limited) or systemic (glandular and systemic involvement) phenotypes. Among 278 patients included, 148 (53%) had a glandular phenotype and 130 (47%) a systemic phenotype. The mean age at diagnosis was 54.6 (± 14.5 years); 95% were women. Sicca symptoms were highly prevalent in both groups (xerophthalmia 89%, xerostomia 84%). In the systemic group, musculoskeletal involvement was most common, particularly arthritis (38%), followed by cutaneous manifestations (26%), cytopenias (19%), pulmonary involvement (16%), and renal or central nervous involvement (5%). ESSDAI scores were significantly higher in patients with systemic involvement (13.9 ± 21.7 vs. 4.0 ± 7.9; p < 0.001). Immunological profiles were similar across phenotypes. Lymphoma occurred in 15 patients (5%), predominantly in patients with systemic involvement (10% vs. 1%; p = 0.001), mostly non-Hodgkin lymphoma. Immunosuppressive therapy was more commonly used in patients with systemic involvement. Adequate stratification of pSjD according to presence or absence of systemic manifestations is mandatory. Our results encourage a close follow-up of systemic pSjD phenotype, particularly for early diagnosis of lymphoma.
Immune cells involved in pain has received increasing attention, but the available literature on the role of T cells in temporomandibular disorders (TMD) related pain is limited. Our previous study has showed that elevated expression of HLA DR+ CD4+ T cell may increase the risk of TMD-related pain. In the present study, we aimed to investigate CD4+ T cell-mediated systemic and local immune changes in the rat model of TMD-related pain via CD4+ T cell depletion, and clarify the immunological contribution of CD4+ T cell on TMD-related pain. A rat model of occlusal interference was established to induce TMD-related pain. Animals were divided into three Groups: control (Group1), occlusal interference (Group2), and occlusal interference with CD4⁺ T cell depletion (Group3). Systemic CD4⁺ T cell proportions were verified by flow cytometry at day3, 6, 14. Pain-related behavior was assessed by von Frey testing daily, and the circulating levels of cortisol, TNF-α, IL-6, IL-17 A, and IFN-γ levels quantified by ELISA at day 3, 10, 15. In the end, local inflammatory cytokine expression patterns in condylar tissues were examined by immunofluorescence staining. Occlusal interference model successfully mimicked significant TMD-related pain with a sharply increase reaching its peak at day 6 followed by a gradual decline, but at lower level of pain in Group3. The circulating level of IL-17 A rapidly rise at the initial phase, then stabilized and declined eventually despite of CD4⁺ T cell depletion or not. Levels of cortisol and TNF-α were significantly decreased at the end of the study in Group 3. Immunofluorescence analysis of condylar tissues revealed substantial up-regulation of TNF-α, IL-6 and IFN-γ in Group 2, which was significantly alleviated in Group 3. This study demonstrated IL-17 A increased with pain independent of CD4+T cells at the early stage. But consistently lower pain sensitivity, reduced systemic and local inflammatory cytokines in the later were identified after CD4 + T cell depletion. So we suggest that CD4⁺ T cells are important to maintain TMD-related pain and central to the late-phase immunological cascade in this model. More underlying mechanism of CD4⁺ T cells involved in TMD-related pain warrant further investigations.
The β2-adrenergic receptor (β2AR), a pivotal member of the G protein-coupled receptor (GPCR) family, plays a crucial role in cellular signaling and is extensively involved in many physiological and pathological processes. Unlike the classical β1AR, the β2AR exhibits unique biased signaling properties. Selective activation of specific downstream pathways, such as the β-arrestin pathway, ERK1/2, and PI3K/Akt, is mediated by ligand binding via biased signaling by a specific G protein, resulting in distinct cellular responses. This review provides an in-depth analysis of the complex mechanisms governing biased β2AR-mediated signaling, highlighting its crucial roles in cardiovascular health, respiratory pathologies, neuroregulatory mechanisms, immunological regulation, and tumor biology. Although β2AR-biased signaling is a well-established phenomenon, its underlying mechanisms and pathophysiological implications remain incompletely elucidated compared with traditional signaling modes. This paper summarizes recent studies on the specificity of β2AR signaling and examines its potential therapeutic applications. Future research should concentrate on clarifying the structural foundations of biased signaling, developing biased ligands, and using these discoveries for precision therapeutics. The therapeutic potential of β2AR-biased signaling is being fully explored, which may open new avenues for personalized treatment of various diseases and bring breakthroughs to the field of clinical medicine.
Type 2 diabetes (T2D) and autoimmune diseases are complex disorders shaped by genetic, immunological, and environmental factors. However, differences in genetic susceptibility to autoimmune disorders between diabetic and non-diabetic individuals remain poorly understood, particularly within the Indian population. This study aimed to compare polygenic susceptibility to multiple autoimmune diseases between individuals with and without T2D from Gujarat, India. Polygenic risk scores were evaluated for eleven autoimmune diseases in 474 individuals, including 99 diabetics and 375 non-diabetics. Significant differences were observed for systemic lupus erythematosus and rheumatoid arthritis. Individuals with diabetes showed a higher genetic risk for systemic lupus erythematosus, whereas non-diabetic individuals exhibited a higher genetic risk for rheumatoid arthritis. Pathway enrichment analysis of disease-associated genetic variants revealed significant involvement of immune-related pathways, including antigen processing and presentation, T-helper cell differentiation, and immune responses to viral infections. The findings reveal disease-specific differences in genetic susceptibility to autoimmune disorders between diabetic and non-diabetic individuals. These results highlight the complex immunogenetic relationship between type 2 diabetes and autoimmune diseases and provide insight into shared and distinct immune pathways within an Indian population. Such information may support future efforts in risk stratification and precision medicine approaches for immune-related comorbidities in diabetes.
Enterovirus D68 (EV-D68) primarily causes respiratory illnesses and has been implicated in acute flaccid myelitis. Although virus-like particle (VLP) and traditional inactivated whole-virion (IWV) vaccines have demonstrated efficacy in mice, their immunological differences remain undetermined. Here, we directly compared the immunogenic and structural properties of VLP and IWV vaccines derived from the same EV-D68 strain under identical conditions. Although VLP induced significantly lower levels of EV-D68-specific IgG than IWV, neutralizing antibody titers and protective effects against viral challenge were comparable between the two groups in mice. Passive transfer experiments in neonatal mice further confirmed protection against lethal infection for both vaccine groups. Notably, in contrast to the IWV vaccine, the VLP vaccine elicited antibodies that preferentially recognized a limited subset of epitopes. Cryo-electron microscopy analyses revealed that VLPs structurally resemble the native virus but display distinct features in regions corresponding to epitopes that show differential antibody reactivity between VLP and IWV vaccines. By integrating structural and immunological analyses, we established a mechanistic framework linking capsid architecture to vaccine-induced antibody specificity. These findings suggest that VLP is a promising EV-D68 vaccine antigen with distinct epitope recognition profiles driven by structural characteristics.