Search Results (293)

Background: Psoriasis frequently relapses after treatment withdrawal, consistent with persistent epigenetic programs in lesional immune cells. Lysine acetylation is a reversible regulatory layer linking chromatin accessibility, transcription factor activity, and immune-cell effector programs; yet, its cell-type-resolved landscape and clinical stratification value in psoriasis remain incompletely defined. Methods: We integrated four bulk transcriptome cohorts of psoriatic and healthy skin (746 psoriasis, 515 controls) with two public skin scRNA-seq datasets. A diagnostic acetylation-regulator signature was derived from 33 curated acetylation regulators, and acetylation endotypes were defined by unsupervised clustering. The cell-type-specific expression was mapped at the single-cell resolution. Key regulators were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in an imiquimod-induced psoriasis-like mouse model, and further verified in an independent dataset (GSE136757). Motif enrichment and drug–target mining were used to prioritize transcriptional regulators and candidate epigenetic therapeutics. Results: Sixteen acetylation regulators were differentially expressed in bulk skin, with histone deacetylase (HDAC1) showing the strongest upregulation and lysine acetyltransferase (KAT2A) the strongest downregulation. A 13-gene acetylation signature discriminated psoriasis from controls (area under the curve, AUC 0.886) and separated lesional samples into two acetylation endotypes with divergent pathway states (hypoxia–glycolysis versus oxidative-stress-dominated programs). Single-cell mapping demonstrated immune-restricted acetylation modules, including CREB binding protein (CREBBP)-enriched neutrophils, histone deacetylase 1 (HDAC1)-high cluster of differentiation (CD)8⁺ T cells, and lysine acetyltransferase 6A (KAT6A)/lymphoid enhancer binding factor (LEF1)-enriched CD4⁺ and regulatory T cell (Treg) subsets, coincident with interleukin (IL)-17-related inflammatory programs. In mice, qRT-PCR confirmed the coordinated dysregulation of hub genes and highlighted Hnf1a and Kat6a as reproducible candidates. External validation using the GSE136757 dataset further supports their robust diagnostic performance. Motif analysis nominated interferon regulatory factor (IRF4), YY transcription factor (YY2), and zinc finger protein (ZNF404) as putative transcriptional mediators downstream of acetylation programs, and drug–target mining prioritized epigenetic compounds with subtype-relevant potential, including histone deacetylase (HDAC) inhibitors (e.g., entinostat) and the p300/CREB binding protein (CBP) inhibitor A485. Conclusions: This integrative atlas links acetylation regulators to specific immune compartments, defines acetylation endotypes associated with distinct inflammatory programs, and provides a rationale for stratified epigenetic target selection in psoriasis. Full article

Plaque psoriasis (PP) is a chronic immune-mediated skin disorder characterized by T-cell dysregulation and an imbalance between regulatory T cells (Treg) and T helper 17 (Th17) cells. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a key inhibitory checkpoint molecule expressed on Treg cells, and its soluble isoform (sCTLA-4) are critical regulators of peripheral immune tolerance and may contribute to PP pathogenesis. This case–control study evaluated the association between the +49 A>G variant of the CTLA4 gene (rs231775) and susceptibility to PP in a mestizo population from western Mexico and assessed serum sCTLA-4 levels. A total of 204 patients with PP and 214 control subjects (CS) were genotyped using PCR-RFLP, and sCTLA-4 concentrations were measured by ELISA. The AG genotype was the most frequent in both groups (49% in PP and 53% in CS), with no significant differences in genotype or allele distributions. Serum sCTLA-4 levels were significantly higher in CS compared to patients (p < 0.05), and no genotype-dependent differences were observed. The rs231775 variant was not associated with PP susceptibility in this population. However, reduced circulating sCTLA-4 levels in patients suggest impaired CTLA-4-mediated immune regulation independent of this variant. Full article

Objectives: This study aimed to assess the effects of voluntary exercise on type 1 diabetes mellitus (T1D) development and splenic immunological profiles in non-obese diabetic (NOD) mice, a spontaneous model of human T1D. Methods: Prediabetic female NOD mice were randomly assigned to sedentary or exercise groups, with mice in the exercise group given 10-week wheel access and sedentary mice receiving none. Late-time mice were monitored to diabetes onset or 24 weeks of age; early-time mice were analyzed immediately post-intervention. Blood glucose, food intake, water consumption, and body mass were monitored weekly. At the endpoints, splenocyte counts, T and B cell subsets, and mitogen-stimulated cytokine production were analyzed using flow cytometry. Results: Mice in the exercise group ran an average of 20.76 ± 0.22 km/day. By the late-time endpoint, 75% of mice in the exercise group remained non-diabetic versus 35% of sedentary mice (p = 0.006). Mice in the exercise group demonstrated lower blood glucose (p = 0.015), visceral fat mass (p = 0.035), and water intake (p < 0.001) but higher food intake (p = 0.001), with no difference in body mass (p = 0.389) compared to sedentary mice. No differences were observed in splenocyte counts or Th, Tc, Treg, or B cell populations at either time point (p ≥ 0.185). Early-time point cytokines also did not differ between groups (p ≥ 0.08). Conclusions: Voluntary exercise reduces T1D incidence and mitigates hyperglycemia in NOD mice, suggesting a protective effect against disease progression. Despite the benefits, physical activity did not alter splenic Tcell subsets or inflammatory cytokines, demonstrating systemic immunomodulation may not be the primary driver of benefit. Our results indicate that voluntary exercise protects against T1D through tissue-specific or metabolic mechanisms, which warrant further mechanistic investigation. Full article

Bronchoscopic cryotherapy is routinely used for endobronchial tumor debulking, but may also exert systemic immunologic effects that could interact with immune checkpoint blockade. We investigated peripheral blood T-cell dynamics following bronchoscopic cryotherapy and subsequent pembrolizumab-based first-line therapy in metastatic non-small-cell lung cancer (NSCLC). In this prospective, randomized, controlled single-center study, patients with metastatic NSCLC were randomized into treatment groups of bronchoscopic cryotherapy performed 7 (±1) days before standard-of-care pembrolizumab (with or without platinum-based chemotherapy) or to standard-of-care therapy alone. Peripheral blood mononuclear cells were analyzed by flow cytometry at baseline, week 3, and week 6. Radiologic response was assessed using RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan–Meier test and Cox regression. Flow cytometry was performed on 34 cryotherapy and 42 control patients. The cryotherapy group demonstrated a decrease in circulating CD4+ T cells (p = 0.002) and an increase in circulating CD8+ T cells (p = 0.013) by week 6. CD25+FOXP3+CD4+ Tregs decreased from baseline to week 3 (p = 0.024) and remained reduced through week 6. Overall response rate was higher in the cryotherapy group (41.2% vs. 16.7%; p = 0.022), while PFS and OS were numerically longer, although not statistically different (median PFS 9.5 vs. 5.3 months; median OS 17.6 vs. 14.8 months). The decrease in Tregs at week 3 was observed to predict better PFS. In patients with metastatic NSCLC receiving first-line pembrolizumab with or without chemotherapy, the addition of bronchoscopic cryotherapy was associated with a detectable peripheral immune remodeling and a higher objective response rate, whereas PFS and OS were numerically longer but not statistically different. Full article

Myeloid differentiation factor 88 (MyD88) signaling plays a central role in inflammatory pathway activation. Adipose-derived interleukin-10 (IL-10), which is induced by insulin and lipopolysaccharides, suppresses hepatic glucose production. This study investigated the role of MyD88/IL-10 signaling in diabetes-induced systemic inflammation and hepatic gluconeogenesis. Stromal vascular fractions (SVFs) were isolated from the adipose tissue of Lepr^db/db and Lepr^db/dbMyD88^−/− mice and treated with IL-10 followed by analysis of inflammatory cytokine expression. IL-10 (10 or 50 ng) was injected into adipose tissue of type 2 DM (T2DM) (Lepr^db/db) mice to investigate its effect on blood dipeptidyl peptidase-4 (DPP4) activity, insulin resistance, and hepatic gluconeogenic signaling. Hepatic inflammatory markers, gluconeogenic gene expression, and metabolic parameters were assessed. Compared with wild-type mice, Lepr^db/db mice exhibited significantly reduced FOXP3 protein expression and IL-10 levels in adipose tissue, accompanied by increased blood DPP4 activity and adiponectin levels, elevated hepatic inflammatory cytokines, and increased G6pc and Pck1 mRNA expression. In contrast, Lepr^db/dbMyD88^−/− mice showed increased Foxp3 protein and PDGFα mRNA expression, decreased IL-6 and CCL2 mRNA expression in SVFs, increased IL-10 levels in adipose tissue, and lower blood adiponectin and ALT levels. MyD88 deletion also attenuated Kupffer cell accumulation, hepatic inflammatory cytokine expression, and gluconeogenic gene expression. In vitro, IL-10 treatment of SVFs from Lepr^db/db mice significantly reduced IL-6 and CCL2 expression and increased Foxp3 mRNA expression. In vivo, adipose IL-10 injection increased Foxp3 and IL-10 expression, expanded Treg cells in SVFs, and activated hepatic Akt signaling, while suppressing pJNK and pNF-κB signaling. These changes were accompanied by reduced blood DPP4 activity, ALT and adiponectin levels, decreased Kupffer cell-derived inflammatory cytokines, reduced hepatic G6pc and Pck1 expression, and improved glucose tolerance. MyD88 signaling induces adipose IL-6 and CCL2, liver inflammation and gluconeogenesis, and blood DPP4 activity by reducing IL-10 and Foxp3 of adipose tissue in T2DM. Enhancing adipose IL-10 induces Treg expansion, inhibits JNK and NF-κB signaling, and alleviates hepatic gluconeogenesis and insulin resistance. MyD88 inhibition or IL-10 elevation in adipose tissue may represent a novel strategy for metabolic syndrome. Full article

Abnormal intestinal mucosal immunity plays a crucial role in ulcerative colitis (UC). Autotaxin (ATX) can promote T cell migration and was reported to have a regulatory effect on Th17 cells, while sphingosine-1-phosphate (S1P) and its receptors (S1PRs) modulate Th17/Treg balance and inflammation, with S1PR modulators approved for UC. ATX can catalyze sphingosylphosphorylcholine (SPC) to produce S1P; however, the relationship between ATX and S1P/S1PRs in UC is unclear. Understanding the role of ATX-S1P/S1PRs in intestinal immunity can provide new treatment strategies for intestinal inflammatory diseases. Both UC patients and DSS-induced colitic mice showed significantly increased levels of ATX and S1P compared with healthy controls. ATX inhibitor PF8380 treatment led to reduced levels of S1P/S1PRs in colitic mice. Consistent with this, the S1PR antagonist etrasimod was able to alleviate ATX-induced intestinal inflammation, as well as partially restore ATX-induced Th17/Treg imbalance in MLNs and the spleen. In HT-29 and Raw246.7 cells, ATX treatment led to enhanced expression of S1P/S1PRs, with S1PR1 being the most significant. Furthermore, S1PR1 mediates the effect of ATX on Th17/Treg cell differentiation and function in vivo. Therefore, ATX affects the differentiation and function of Th17/Treg cells through S1P/S1PR1 signaling, increased ATX expression leading to Th17/Treg cell imbalance, intestinal mucosal immune dysfunction, and exacerbating intestinal inflammation. Full article

The appearance of antibiotic-resistant strains of Helicobacter pylori (H. pylori) is leading to a decreased eradication rate of H. pylori infection. There is an urgent need to find new agents with antimicrobial mechanisms different from those of antibiotics, with therapeutic potential to clear colonization of H. pylori in the stomach. Some antimicrobial peptides (AMPs) possess bactericidal activity by enhancing the permeability of the outer membrane and damaging the integrity of the cell membrane. Bacteria are not susceptible to drug resistance through this antimicrobial mechanism. In this study, 28 short peptides containing 12 amino acid residues were designed based on nine amino acid fragments (KRIVQRIKD) from human cathelicidin LL-37, which is stable in gastric juice, and 3 amino acids were added at the C-terminus of the peptide. These designed peptides were not digested and degraded by pepsin at low pH values. The peptides were predicted using the online tool platform. Then, the strongest antimicrobial peptide, named SAMP-12aa (KRIVQRIKDVIR), was screened from 28 short peptides. Further studies found that SAMP-12aa retained anti-H. pylori activity after incubation in simulated gastric juice. The MIC and MBC of SAMP-12aa were 8 μg/mL and 32 μg/mL, respectively. SAMP-12aa showed good bactericidal kinetics. SAMP-12aa was found to have cell selectivity, penetrating and damaging bacterial cell membranes and exhibiting almost no toxicity to human cells at a relatively high concentration (128 μg/mL). Regulatory T (Treg) cells express CD25^High with immunosuppressive activity that induces immune tolerance in response to H. pylori. Molecular docking prediction revealed that SAMP-12aa could target the active center of Foxp3. Flow cytometry analysis revealed that SAMP-12aa can inhibit Foxp3 activity and downregulate CD25 protein expression on CD4⁺ T cells, thereby reducing the development and differentiation of CD4⁺Foxp3⁺CD25^High Treg cells with immunosuppressive effects. Further research revealed that the levels of the cytokine interferon-γ (IFN-γ), which activates CD8⁺ T-cell activity, were significantly elevated, and the levels of transforming growth factor-β (TGF-β), which inhibits CD8⁺ T-cell activity, were significantly reduced. The results of this study reveal that SAMP-12aa not only possesses antibacterial activity but also has immunomodulatory effects. Full article

Alcohol-associated hepatitis (AH) is the most severe clinical manifestation of alcohol-associated liver disease. Corticosteroids are the only disease-specific therapy shown to improve short-term survival. Currently, no non-invasive markers are available to predict patient response to corticosteroids or long-term survival in AH. This study investigates whether surface antigens on plasma extracellular vesicles (EVs), key mediators of intercellular communication, can reflect the underlying immune dysregulation in AH and serve as prognostic markers. Patients with AH were prospectively enrolled between 2020 and 2024. Blood samples were collected before corticosteroid initiation during the first 24 h of hospitalization. EVs were characterized using nanoparticle tracking analysis, cryo-electron microscopy, and flow cytometry. Interleukin-6 (IL-6), soluble (s)CD62p, Circulating Vascular Cell Adhesion Molecule-1 (sVCAM), tumor necrosis factor receptor superfamily member 1 (TNRFS1a), and Intercellular Adhesion Molecule 1 (ICAM-1) were quantified by ELISA. Key outcome variables included response to corticosteroids and mortality. A total of 46 patients with AH and 28 healthy donors (HD) were included. EV concentration was significantly higher in AH patients than in HD (9.3 × 10¹¹ [IQR 4–24] versus 2.4 × 10¹¹ [IQR 2–4], p = 0.03). Specific EV antigens were associated with key clinical outcomes: CD20 and CD2 levels differed between patients with or without infections (bacterial, viral, and fungal) developed during hospitalization; CD40 and CD146 were elevated in patients who developed acute kidney injury. EVs enriched in monocyte (CD14) and T-reg (CD25) markers were associated with plasma IL-6 levels, while endothelial markers CD105 and CD146 correlated with sVCAM and sCD62p. EVs enriched in platelet (CD49e) and endothelial (CD31) markers were associated with corticosteroid response, whereas EVs enriched with endothelial (CD105 and CD146) and B lymphocyte (CD19) markers were associated with mortality. Overall, EVs enriched in endothelial and monocyte markers may represent a candidate non-invasive tool for predicting corticosteroid response and mortality in AH, aiding risk stratification and early identification of non-responders for timely transplant evaluation. Full article

Background/Objectives: Allergic rhinitis (AR) is a complex immune-mediated disorder characterized by defective regulatory mechanisms. Emerging evidence suggests that impaired immune tolerance mediated by regulatory B cell (Breg) plays a pivotal role in AR pathogenesis. This study investigates the therapeutic potential of Der p1 allergen-modified dendritic cells (DC) in enhancing Breg-mediated immunotherapy and explores novel mechanisms underlying AR immunomodulation. Methods: Breg and the inflammatory cytokines were detected before and after allergen immunotherapy (AIT) in AR patients. Dust mite gene-derived dendritic cells were used to induce Breg. AR mice were treated with Der p1-DCs, and changes in Breg and related inflammatory indicators, as well as the impact of the IL-10/STAT pathway on DC vaccine treatment, were observed. Results: Following 6-month AIT, AR patients exhibited significant alleviation of nasal symptoms alongside restored peripheral Breg and Treg. In vitro co-culture of Der p1-DC-induced Bregs with CD4⁺CD25⁻T cells revealed that IL-10 blockade markedly increased Th cell. In AR murine models, intraperitoneal Der p1-DC administration suppressed allergic symptoms, upregulated nasal mucosal IL-10 expression, and attenuated STAT3 phosphorylation via IL-10 overexpression. Conclusions: AIT establishes immune tolerance through Breg-mediated regulatory mechanisms, while Der p1-DCs potently induce Breg differentiation and drive tolerance induction via the IL-10/STAT3 signaling axis. Full article

Background: Small-cell lung cancer (SCLC) is an aggressive type of lung cancer, and several factors are currently used to predict poor outcomes, including performance status (PS), extensive-stage disease, male sex, advanced age, and elevated lactate dehydrogenase (LDH) levels. In this study, we aimed to explore the role of Tegs and inflammatory indices, such as CRP and NLR, in predicting response to immunotherapy. Methods: Fifty-one therapy-naïve ES-SCLC patients and ten healthy donors were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with fluorochrome-conjugated monoclonal antibodies. Multicolor flow cytometry was performed to determine the levels of CD8⁺ T cells and CD4⁺ Tregs, as well as their correlation with inflammatory indices and clinical outcomes. Results: ES-SCLC patients harbored higher percentages of CD8⁺ Teffs (p = 0.005) and FOXP3⁺ Tregs (p < 0.0001) in circulation before therapy compared with healthy donors. In addition, high levels of CD3⁺CD8⁺ T effectors were associated with longer PFS (p = 0.018) and longer OS (p = 0.012) compared with patients bearing low levels, while Tregs were not found to be predictive. More importantly, a survival benefit was observed in ES-SCLC patients with a low Treg/Teff ratio, as longer OS was observed in those with high percentages of CD8⁺ Teffs and low FOXP3⁺CTLA-4⁺ Tregs (p = 0.014) compared with those bearing low CD8⁺ Teffs and high FOXP3⁺CTLA-4⁺ Tregs. A low Treg/Teff ratio was further associated with low eosinophil levels and a low NLR before treatment initiation. Conclusions: These findings suggest a novel, easily obtainable blood-based signature that may help predict response to ICIs in ES-SCLC patients. Full article

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition resulting from dysregulation of the intestinal immune system. CD4⁺FoxP3⁺ regulatory T cells (Tregs) play a crucial role in regulating this immune response. The heat shock response (HSR) regulates the inflammatory cascade, preventing misfolding of proteins and regulating immune responses. We have previously shown that Heat Shock Factor 1 (HSF1), the master regulator of the HSR, regulates Tregs in inflammation. Based on this finding, we hypothesized that targeting HSF1 with celastrol, a pentacyclic triterpenoid that activates HSF1, would activate Treg cells and ameliorate intestinal inflammation. To test this, we investigated the impact of celastrol on Tregs both in vitro and in vivo, evaluating its efficacy in HSF1^fl/fl-CD4^cre mice, and in two murine models of IBD: the adoptive transfer colitis, and TNF^ΔARE+/− ileitis. Our results demonstrate that celastrol activates HSF1 in Tregs, enhances Treg suppressive function, increases Treg populations in vivo, and ameliorates intestinal inflammation. Full article

Objective: This study investigated whether rapamycin could modulate the polarisation of CD4+ T cells towards T_H1, T_H2, T_H17, and Treg cells using peripheral blood mononuclear cell (PBMC) obtained from patients with granulomatosis with polyangiitis and microscopic polyangiitis (GPA/MPA). Methods: Twenty patients with GPA/MPA were included in this study. Their stored PBMCs were cultured and stimulated with anti-CD3 and anti-CD28 antibodies for 72 h in the presence or absence of rapamycin (10 nM). The cells were stained for surface markers with anti-CD4-FITC and anti-CD25-APC, followed by intracellular staining using anti-interferon (IFN)-γ-PE, anti-IL-4-PerCP-Cy5, anti-IL17A-APC, and anti-Foxp3-PE. The stained cells were analysed using a flow cytometer. Results: The median age of the 20 GPA/MPA patients (10 men and 10 women) was 65.5 years. Rapamycin treatment significantly modulated the polarisation of CD4+IFN-γ+ T (T_H1) cells compared to no treatment among GPA/MPA patients. In addition, the polarisation of CD4+IFN-γ+ T (T_H1) cells was also significantly reduced in rapamycin-treated PBMC obtained from active patients compared to untreated PBMC from the same patients; however, these alterations were not observed in inactive patients. Conversely, rapamycin treatment did not affect the polarisation of CD4+IL-4+ T (T_H2), CD4+IL-17+ T (T_H17), or CD4+FoxP3+CD25+ T (Treg) cells, regardless of GPA/MPA activity. Conclusions: This study was the first pilot study to demonstrate that rapamycin modulates the polarisation of CD4+ T cells towards CD4+IFN-γ+ T cells in active GPA/MPA. Full article

Background/Objectives: Acute pneumonia remains one of the leading causes of mortality worldwide. The pathogenesis of the disease is determined by the nature of the host immune response. The balance between effector and regulatory T cells (Treg) is critical, as it determines the severity of inflammation and the regenerative capacity of lung tissue. The development of new approaches to modulate the immune response using promising synthetic compounds opens up the possibility of targeted cytokine balance restoration of cytokine balance and Tregs functions This study investigated the effects of the newly synthesized complex of 1-(2-Ethoxypropyl)-4-(pent-1-yn-1-yl)piperidin-4-yl Propionate with β-Cyclodextrin (MXF-22), on the populations of CD4⁺, CD4⁺CD25⁺ and CD4⁺FoxP3⁺ T cells in an oleic acid-induced acute lung injury rat model. Methods: Quantitative analysis of CD4⁺, CD4⁺CD25⁺, and CD4⁺FoxP3⁺ T cell subsets and serum IL-4 and TGF-β levels were determined by flow cytometry and ELISA assays, respectively. Results: The study revealed a significant decrease in the number of CD4⁺ T cells and their regulatory subsets (CD4⁺CD25⁺, CD4⁺FoxP3⁺) during acute pneumonia. Oral administration of MXF-22 contributed to a pronounced recovery of these parameters, accompanied by increased levels of IL-4 and TGF-β, which indicated the activation of anti-inflammatory and reparative processes. Conclusions: MXF-22 showed a pronounced immunomodulatory effect contributing to the restoration of the function of CD4⁺ FoxP3⁺ T regs in acute pneumonia rat model. Full article

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG–PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG–PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving apoptosis and autophagy, while miR-142 suppressed PD-L1 expression and epithelial–mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4⁺ and CD8⁺ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors. Full article

Background/Objectives: To investigate the relationship between patient age and the clinical efficacy of subcutaneous immunotherapy (SCIT) for allergic rhinitis (AR), aiming to provide a reference for patient selection and efficacy improvement in clinical practice. Methods: We conducted a retrospective statistical analysis of clinical data from 240 AR patients who underwent standardized house dust mite (HDM) SCIT for at least 6 months at our hospital between 2019 and 2025. Patients were stratified into four age groups (children, young adults, middle-aged adults, and the elderly) according to the World Health Organization (WHO) classification. The clinical efficacy, nasal symptom scores, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, peripheral blood regulatory T cell (Treg) and regulatory B cell (Breg) levels, and adverse reactions were analyzed across these age strata. Additionally, to investigate the underlying mechanisms, we utilized a public single-cell transcriptomic dataset (GSE176269; n = 35, age 4 months-65 years) to assess the relationship between T cell senescence and age through data integration and senescence gene set scoring. For multiple comparisons, the significance level was adjusted using the Bonferroni method. This adjustment ensured the overall significance level (α) of the study was maintained at 0.05, and the final adjusted significance level (α′) for each age group was 0.0125. Results: The overall response rate for the entire cohort was 62.5%. Age-stratified analysis revealed a significantly higher response rate in children (83.3%) compared to middle-aged and elderly patients (48.5% and 20%, respectively), with the difference being statistically significant (p < 0.001). Following treatment, both total nasal symptom scores and RQLQ scores decreased significantly across all age groups compared to baseline (p < 0.001). Peripheral blood Treg and Breg levels increased post-treatment in all age groups; however, the increase was not statistically significant in the middle-aged and elderly groups (p > 0.0125). The incidence of systemic adverse reactions was 4.17% (all Grade I), occurring primarily in the child and young adult groups, but the difference among age groups was not statistically significant (p > 0.0125). Mechanistically, our single-cell analysis revealed that T cells within the nasal mucosa exhibit significant age-dependent senescence. Conclusions: SCIT is a safe and effective treatment for AR across all age groups. However, pediatric patients appear to derive greater benefit compared to middle-aged and elderly patients, a finding that corresponds with age-stratified immunological data. Therefore, different efficacy expectations should be considered when selecting SCIT for patients of varying ages, and future research should explore strategies targeting T cell senescence to enhance desensitization efficacy in elderly patients. Full article