Search Results (670)

Hypoxia, oxidative stress, and impaired protein folding contribute to tumor progression and therapy resistance. Endoplasmic Reticulum Oxidoreductin 1 Alpha (ERO1α) is a key enzyme regulating redox homeostasis in the endoplasmic reticulum by reoxidizing protein disulfide isomerase, facilitating disulfide bond formation, and generating reactive oxygen species. Elevated ERO1α levels are associated with increased tumor aggressiveness, metastasis, and poor clinical outcomes. Despite growing evidence of its tumor-promoting functions, no clinically approved ERO1α inhibitors exist. This systematic review provides a comprehensive and integrative analysis of current research on ERO1α in breast cancer, emphasizing its roles in hypoxia response, angiogenesis, immune modulation, and ferroptosis resistance. We discuss mechanistic links, including VEGF-A maturation and PD-L1-mediated immune evasion, and highlight recent advances in small-molecule ERO1α inhibitors and preclinical therapeutic strategies. By consolidating molecular insights and translational considerations, this review underscores ERO1α as both a promising therapeutic target and potential prognostic marker, offering guidance for future drug development and targeted interventions in redox-dependent cancer pathways. Full article

Background: Aryl hydrocarbon receptor (AhR) is a transcription factor that is involved in the regulation of immunity. AhR inhibits T cell activation in tumors, which induces immune suppression in the blood and solid tumors. We identified effective small-molecule AhR antagonists for cancer immunotherapy. Methods: A new series of pyrazolopyrimidine derivatives was synthesized and evaluated for AhR antagonistic activity. Results: Compound 7k exhibited significant antagonistic activity against AhR in a transgenic zebrafish model. In addition, 7k exhibited good AhR antagonist activity, with a half-maximal inhibitory concentration (IC₅₀) of 13.72 nM. Compound 7k showed a good pharmacokinetic profile with an oral bioavailability of 71.0% and a reasonable half-life of 3.77 h. Compound 7k selectively exerted anti-proliferative effects on colorectal cancer cells without affecting normal cells, concurrently suppressing the expression of AhR-related genes and the PD-1/PD-L1 signaling pathway. Compound 7k exhibited potent antitumor activity in syngeneic colorectal cancer models. Importantly, the combination of anti-PD1 and compound 7k enhanced antitumor immunity by augmenting cytotoxic T lymphocyte (CTL)-mediated activity. Conclusions: Collectively, a new pyrazolopyrimidine derivative, 7k, shows promise as a potential therapeutic agent for treating colorectal cancer. Full article

Background: Oncolytic virus (OV) therapy couples direct tumor lysis with systemic immune priming, yet clinical benefit remains heterogeneous and the predictive biomarker landscape is poorly defined. We undertook a systematic review and meta-analysis to quantify the efficacy and safety of OV therapy in solid tumors and to synthesize current evidence on response-modulating biomarkers. Methods: Following PRISMA 2020 guidelines, MEDLINE, Embase, Cochrane CENTRAL, ProQuest and Scopus were searched from inception to May 2025. Phase II–III randomized trials of genetically engineered or naturally occurring OV reporting objective response rate (ORR), progression-free survival (PFS), overall survival (OS) or biomarker data were eligible. Hazard ratios (HRs) or odds ratios (OR) were pooled with random-effects models; heterogeneity was assessed with I² statistics. Qualitative synthesis integrated genomic, immunologic and microbiome biomarkers. Results: Thirty-six trials encompassing around 4190 patients across different tumor types met inclusion criteria. Compared with standard therapy, OV-based regimens significantly improved ORR nearly three-fold (pooled OR = 2.77, 95% CI 1.85–4.16), prolonged PFS by 11% (HR = 0.89, 95% CI 0.80–0.99) and reduced mortality by 16% (OS HR = 0.84, 95% CI 0.72–0.97; I² = 59%). Benefits were most pronounced in melanoma (ORR 26–49%; OS HR 0.57–0.79) and in high-dose vaccinia virus for hepatocellular carcinoma (HR = 0.39). Grade ≥ 3 adverse events were not increased versus control (risk ratio 1.05, 95% CI 0.89–1.24); common toxicities were transient flu-like symptoms and injection-site reactions. Biomarker synthesis revealed that high tumor mutational burden, interferon-pathway loss-of-function mutations, baseline CD8⁺ T-cell infiltration, post-OV upregulation of IFN-γ/PD-L1, and favorable gut microbial signatures correlated with response, whereas intact antiviral signaling, immune-excluded microenvironments and myeloid dominance predicted resistance. Conclusions: OV therapy confers clinically meaningful improvements in tumor response, PFS and OS with a favorable safety profile. Integrating composite genomic–immune–microbiome biomarkers into trial design is critical to refine patient selection and realize precision viro-immunotherapy. Future research should prioritize biomarker-enriched, rational combination strategies to overcome resistance and extend benefit beyond melanoma. Full article

Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus’s epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed cell death protein ligand 1 (PD-1/PD-L1) pathway have shown promise in advanced TC, potentially benefiting from frequent PD-L1 overexpression and abundant CD8⁺ tumor-infiltrating lymphocytes (TILs), despite typically low tumor mutational burden (TMB). While ICI monotherapy can achieve disease control in some patients, its overall efficacy is limited and it is associated with a distinct profile of immune-related adverse events (irAEs) which occur less often than in thymomas. The predictive value of biomarkers—particularly PD-L1 expression—remains uncertain, underscoring the importance of consistent assessment criteria. In this review, we summarize evidence on ICI monotherapy as well as combination approaches that incorporate anti-angiogenic agents, chemotherapy, or dual checkpoint blockade. Emerging therapeutic targets—such as CD70, TIM-3, and B7-H4—are also considered in the context of their potential clinical relevance. Finally, we discuss future directions aimed at improving efficacy, extending response durability, and reducing treatment-related toxicity through biomarker-based patient selection and tailored therapeutic strategies. Full article

Methane dry reforming (DRM) represents a promising route for the simultaneous valorization of CH₄ and CO₂ into syngas; however, conventional Ni-based catalysts suffer from rapid deactivation due to sintering and carbon deposition. In this work, we present a synergistically engineered Ni-based catalyst integrating hierarchical SiC confinement, Pd promotion via oleic-acid-assisted complexation, and MgO surface modification to overcome these challenges. Under optimized reaction conditions (CH₄/CO₂ = 1:1, 750 °C, GHSV = 36,000 mL g⁻¹ h⁻¹), the multifunctional NiPd/Si–xMg catalyst achieved steady-state conversions of 85% for CH₄ and 84% for CO₂, maintaining an H₂/CO ratio close to 1.0 over 100 h of continuous operation without noticeable deactivation. In contrast, the reference Ni/SiC and Ni/MgO catalysts exhibited initial conversions of 75–80% but declined by more than 50% within the same period, confirming the superior durability of the optimized system. Thermogravimetric analysis (TGA) revealed a drastic reduction in carbon deposition—from 119.0 mg C g⁻¹ for Ni/SiC to 81.4 mg C g⁻¹ for NiPd/Si-xMg—indicating enhanced coke resistance. Transmission electron microscopy (TEM) confirmed uniform Ni dispersion with an average particle size of 7.2 ± 1.8 nm, while H₂-TPR and CO₂-TPD analyses demonstrated improved reducibility and surface basicity. The combination of SiC confinement, Pd-induced hydrogen spillover, and MgO-mediated CO₂ activation effectively mitigated sintering and carbon accumulation, resulting in high activity, stability, and carbon tolerance. This integrated catalyst design provides a robust pathway toward industrially viable DRM systems for sustainable syngas production. Full article

Background: Immune dysregulation has emerged as a central mechanism in atrial fibrillation (AF), with accumulating evidence implicating T-cell subsets, cellular senescence, checkpoint dysfunction, and inflammatory signaling. Although individual studies have provided important insights, a comprehensive synthesis across histological, mechanistic, prognostic, and genetic domains has been lacking. Methods: We systematically reviewed 16 studies published between 2009 and 2025, encompassing histological investigations, translational and mechanistic analyses, interventional cohorts, prognostic studies, and Mendelian randomization. Data on immune cell subsets, cytokines, signaling pathways, and clinical outcomes were extracted. Risk of bias was assessed using ROBINS-I and RoB 2, while certainty of evidence was graded using the GRADE framework. Results: Histological studies consistently demonstrated infiltration of atrial tissue by T lymphocytes and macrophages, with greater intensity in persistent and permanent AF, causally linked to atrial dilatation and fibrosis. Epicardial adipose tissue emerged as a key reservoir of tissue-resident memory T cells that promote IL-17- and IFN-γ-mediated fibroinflammatory remodeling. Mechanistic analyses highlighted CD8⁺PAR1⁺ cytotoxic T cells, PD-1/PD-L1 checkpoint disruption, and adipose–myocardial crosstalk as pivotal drivers of AF. Prognostic studies indicated that immune biomarkers provide incremental predictive value beyond conventional risk scores, while genetic evidence supported a causal role for immune dysregulation in AF susceptibility and progression. Conclusions: Across multiple levels of evidence, immune dysregulation is a primary determinant of AF development, progression, and outcomes. Integration of immune biomarkers into clinical practice may enhance risk stratification and inform the design of immune-targeted therapies for atrial fibrillation. Full article

Background: Celiac disease (CD) is a gluten-sensitive immune-related enteropathy of the small intestine characterized by villus atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (IELs). Objectives: To characterize the phenotype of IELs and immune cells of the lamina propria of small intestine control using immuno-oncology and immune-phenotype markers and test the most relevant marker, an immune checkpoint co-inhibitory receptor, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), in CD. Methods: Immunohistochemical analysis of CD3 (CD3E), CD4, CD8, CD103 (ITGAE), Granzyme B (GZMB), TCR beta (β), TCR delta (δ), CD56 (NCAM), CD16 (FCGR3A), LAIR1 (CD305), PD-L1 (CD274), PD1 (CD279), BTLA (CD272), TOX2, HVEM (TNFRSF14), CD163, HLA-DP-DQ-DR, IL4I1, and FOXP3 was performed using histological analysis. Gene expression analysis was performed using an independent dataset to expand and confirm the findings. Results: IELs exhibited a cytotoxic T-cell phenotype and were CD3+, CD8+, CD103+, TCR beta+, and LAIR1+. The lamina propria (LP) was abundant in CD163+, HLA-DP-DQ-DR+, BTLA+, PD-L1+, CD103+, CD56+, and LAIR1+ cells corresponding to macrophages and T- and B-lymphocytes. In CD, IELs and part of the inflammatory cells of the lamina propria cells were LAIR1+. CD was characterized by higher quantity of LAIR1+ IELs and LP immune cells than the small intestine control (p = 0.004). Higher intestinal lesions evaluated by Marsh scoring were correlated with higher LAIR1 (p < 0.001). Gene expression analysis confirmed the overexpression of the LAIR1 pathway in CD and highlighted BTLA. At the protein level, BTLA overexpression was confirmed in CD. Finally, as a proof-of-concept AI analysis, a convolutional neural network classified LAIR1-stained image patches between the three diagnoses of small intestine control, CD, and reactive tonsils with high accuracy (99.6%). Conclusions: IELs exhibit a cytotoxic T-cell phenotype and were found to be CD3+, CD8+, CD103+, TCR beta+, and LAIR1+ in the small intestine control. Increased numbers of LAIR1+ IELs and lamina propria immune cells characterize CD. Full article

Background/Objectives: Monoclonal antibody (mAb) stability is critical not only during manufacturing but also at the point of clinical administration. For therapies like tislelizumab (Tevimbra), a programmed death-1 (PD-1) targeting IgG mAb, delays in dosing often result in prepared infusions being discarded, contributing to substantial drug waste despite being engineered for improved stability. Methods: To evaluate the physicochemical in-use stability of tislelizumab in a ready-to-administer format, we mapped degradation pathways, including post-translational modifications (PTMs); peptide alterations; pH and solution characteristics—under 12-month storage (ultra-long), under 1-month storage (0, 7, 14, 21, 28 and 31 days), and under exposure-related forced degradation conditions including room temperature, elevated temperature, pH (acidic/basic), oxidation and UV exposure. Structural analysis was contextualised to the known PD-1 binding site, making stability assessment relevant to tislelizumab’s mechanism-of-action in blocking PD-1. To assess solution stability, a validated size-exclusion chromatography (SEC) assay was applied to all conditions. Results: Aggregation was identified as the primary degradation pathway during ultra-long-term storage. SEC and chemical assessment revealed no measurable changes in protein quantity, aggregation, peptide integrity, or PTM profile over 31 days at 2–8 °C in polyolefin intravenous bags (1.6 mg/mL). Conclusions: These results support the structural and physicochemical stability of tislelizumab under refrigerated conditions. Full article

Background: Immune checkpoint inhibitors (ICIs) are effective against various advanced and metastatic cancers, but patient responses vary and can change over time, complicating treatment prediction. Therefore, better tools for patient stratification, response prediction, and response assessment are needed. This study presents the development and clinical translation of a fluorescently labelled ICI tracer pair used to perform multispectral fluorescent molecular imaging and simultaneously gain spatial and temporal insight in both programmed death ligand 1 (PD-L1) and programmed death receptor 1 (PD-1) expression. Methods: We conjugated the anti-PD-L1 antibody durvalumab to IRDye 680LT and the anti-PD-1 antibody nivolumab to IRDye 800CW. Tracers were developed and optimized for conjugation efficiency and purity to allow use in clinical trials. Stability was tested up to 12 months. An extended single-dose toxicity study in mice was performed for durvalumab-680LT and the unconjugated IRDye 680LT to demonstrate safety for first-in-human administration. Results: Durvalumab-680LT and nivolumab-800CW were successfully conjugated and purified. Conjugation optimization resulted in a robust production with labelling efficiencies of ≥88%. Long-term stability study of both tracers showed all parameters within end of shelf-life specifications for at least 12 months at 2–8 °C. No toxic effects were observed in doses up to 1000x the intended human dose for both IRDye 680LT and durvalumab-680LT, which are therefore considered safe for first-in-human use. Conclusions: We succeeded in the development and clinical translation of two novel fluorescent ICI tracers, durvalumab-680LT and nivolumab-800CW. Moreover, we demonstrated for the first time the safety of IRDye 680LT and durvalumab-680LT, enabling first-in-human use. Together, this makes durvalumab-680LT and nivolumab-800CW suitable for phase I/II clinical trials. Full article

Despite advances in immunotherapy, the treatment of breast cancer still remains a major global problem. In a previous study, we showed that co-blockade of Interleukin-33/ST2 and Programmed death-1/Programmed death-ligand (PD-1/PD-L) signaling pathways strongly slows progression by enhancing the antitumor capacity of natural killer (NK) cells. The main aim of this study is to elucidate the exact effect of co-blockade on the T lymphocyte and macrophage effector cells. 4T1 cells were used to induct breast cancer in female BALB/C and BALB/C ST2^−/− mice. The mice, both BALB/C and BALB/C ST2^−/−, were treated with anti-PD-1 antibody on certain days. After the mice were sacrificed, T cells and macrophages were analyzed using flow cytometry; dual co-blockade increased significantly the percentage of M1 macrophages in the tumor microenvironment, followed by an increase in expression of CD86⁺ and TNFα⁺. T cell accumulation was significantly higher in the spleen and within the tumor microenvironment, with elevation in activation markers such as Interleukin-17, CD69, NKG2D, and FasL and a decrease in Interleukin-10 and FoxP3 expression. Co-blockade of the PD-1/PD-L axes and IL-33/ST2 axes shows promising results in reestablishing an effective immune response and offers a new perspective on improving immune response to breast carcinoma. Full article

Sialic acid, typically positioned at the terminal ends of glycoprotein or glycolipid chains via glycosyltransferase activity, is indispensable for intercellular recognition and signal transduction. Aberrant sialylation has been implicated in disrupted cell communication and oncogenic signaling, contributing to carcinogenesis. Consequently, targeting sialic acid metabolism has emerged as a promising strategy for cancer diagnosis and therapy. This review first delineates the physiological biosynthesis of sialic acid and molecular mechanisms underlying its pathological dysregulation. We then examine the sialic acid–Siglec axis as an immune checkpoint in cancer immunotherapy, highlighting its functional convergence and divergence from the PD-1/PD-L1 pathway. Furthermore, we elucidate how aberrant sialylation drives malignant transformation. Finally, we synthesize current therapeutic strategies targeting the sialic acid–Siglec axis, with particular emphasis on implementing nanomaterial-based platforms in clinical translation. These advances may yield novel diagnostic tools and therapeutic targets for glycobiology-guided precision medicine. Full article

Salt stress is a major abiotic factor limiting wolfberry (Lycium barbarum) growth. As a high-value medicinal and edible crop, wolfberry relies on its carotenoid content, a critical determinant of fruit quality and nutritional value. To elucidate the expression regulatory mechanisms of key genes in the carotenoid biosynthesis pathway under salt stress, this study systematically identified 17 structural genes within the L. barbarum carotenoid pathway using genomic and transcriptomic approaches. Comprehensive analyses were conducted on gene structure, chromosomal distribution, conserved domains, and cis-acting elements. The results revealed that these genes were clustered on chromosomes Chr08 and Chr10 and exhibit strong collinearity with tomato (18 syntenic pairs). Their promoters were enriched with light-responsive (G-box) and stress-responsive (ABRE, DRE) elements. Tissue-specific expression analysis demonstrated high expression in mid-to-late fruit developmental stages (LbaPSY1, LbaPDS) and in photoprotective genes (LbaZEP, LbaVDE) in leaves. Under 300 mM NaCl stress treatment, the genes exhibited a staged response: Early stage (1–3 h): upstream MEP pathway genes (LbaDXS, LbaGGPS) were rapidly induced to supply precursors. Mid-stage (6–12 h): midstream genes (LbaPSY, LbaPDS, LbaZDS) were continuously upregulated, promoting lycopene synthesis and preferentially activating the β-branch (LbaLCYB). Late stage (12–24 h): downstream xanthophyll cycle genes (LbaBCH, LbaZEP, LbaVDE) were significantly enhanced, facilitating the accumulation of antioxidant compounds like violaxanthin and neoxanthin. This coordinated regulation formed a synergistic “precursor supply–antioxidant product” network. This study revealed the phased and coordinated regulatory network of carotenoid biosynthesis genes under salt stress in L. barbarum. It also provided potential target genes for the new cultivar selection with enhanced salt tolerance and nutritional quality. Full article

Dopamine (DA) replacement by L-DOPA administration is the most common and effective treatment for Parkinson’s disease (PD). However, its chronic use leads to important side effects at advanced stages of the disease. Levodopa-induced dyskinesia (LID), characterized by involuntary, abnormal movements, is the main challenge of L-DOPA treatment. Although the causes underlying LID are not fully understood, abnormal plasticity in corticostriatal synapses and dysregulated DA release from serotonin terminals play a crucial role. In recent years, several studies have suggested the involvement of neuroinflammation and oxidative stress in the pathophysiology of LID. Interestingly, different evidence has shown that blocking these pathways reduces LID in experimental animal PD models, pointing to the use of antioxidant/anti-inflammatory agents as a potential therapy for LID. Numerous studies have shown the role of the brain renin–angiotensin system (RAS) and the ROCK pathway in neuroinflammation and oxidative stress. Compounds acting through these routes have strong neuroprotective properties in PD models. Additionally, the use of ROCK inhibitors, such as fasudil, and RAS blockers has shown potent anti-dyskinetic effects. Therefore, compounds acting on the RAS and ROCK pathways could have a dual role, slowing down the degeneration of dopaminergic neurons and reducing the development of LID. Full article

Background/Objectives: Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous and aggressive lymphoma with a high incidence rate. Although modern therapeutic approaches have significantly improved patient survival rates, treatment relapse and drug resistance remain major clinical challenges. Programmed cell death (PCD) promotes tumorigenesis and regulates the tumor microenvironment (TME) and drug sensitivity. Exploring the application potential of PCD in DLBCL could pave the way for new treatment strategies for this malignancy. Methods: We systematically analyzed 13 types of PCD pathways and integrated transcriptomic and clinical data from 832 DLBCL patients (GSE10846, GSE11318, and GSE87371). A PCD-based prognostic signature, termed the Programmed Cell Death Score (PCDS), was constructed using 20 key PCD-related genes. Its clinical relevance was evaluated through survival analysis, drug response profiling, and tumor immune infiltration assessment using CIBERSORT, ESTIMATE, and ssGSEA algorithms. Results: The PCDS robustly stratified patients by survival and outperformed conventional clinical indicators such as age, stage, Eastern Cooperative Oncology Group (ECOG), and lactate dehydrogenase (LDH) in prognostic prediction. High-PCDS tumors were associated with immune suppression, characterized by reduced CD8⁺ T cell infiltration, elevated M2 macrophages, and increased programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression. Drug sensitivity analysis revealed that high-PCDS patients may benefit more from agents like sorafenib and fulvestrant, while low-PCDS patients responded better to NU7441. Functional validation using DLBCL cell lines and xenografts confirmed the oncogenic role of a representative gene (CTH) within the model. Conclusions: This study presents a novel prognostic scoring system derived from multiple PCD pathways that effectively stratifies DLBCL patients by risk and therapeutic responsiveness. Notably, the PCDS is closely associated with key immunological characteristics of the TME. These findings advance personalized treatment strategies and support clinically relevant decision-making in DLBCL. Full article

Parkinson’s disease, associated with mutations in the GBA1 gene (GBA1-PD), is the most common genetic form of Parkinson’s disease (PD), marked by clinical heterogeneity influenced by mutation type. Extracellular vesicles (EVs), key mediators of intercellular communication, are implicated in PD pathogenesis through the transport of pathological proteins and lipids. In this study, we analyzed blood plasma-derived EVs from GBA1-PD patients carrying p.N370S and p.L444P mutations and from healthy controls using cryo-electron microscopy, lipidomics, and proteomics. EVs from GBA1-PD patients were significantly larger than those from controls, with the largest size and most multilayered vesicles observed in p.N370S carriers. Lipidomic profiling identified 237 lipid species; of these, 186 lipids were altered in p.N370S and 24 in p.L444P versus controls. Mutation carriers showed distinct lipid signatures, with p.L444P samples enriched predominantly in sphingolipids, while p.N370S carriers exhibited more extensive lipid remodeling across multiple classes, including triglycerides, cholesteryl esters, and phospholipids. Notably, Cer 23:0 was elevated across all GBA1-PD groups. Proteomic analysis revealed enrichment in pathways related to lipid transport, immune regulation, and vesicle-mediated processes. Overall, GBA1-PD patients share a distinct lipidomic EV signature, with mutation-specific patterns reflecting differing mechanisms of lysosomal dysfunction. These findings support the potential of EV profiling to unravel disease heterogeneity and identify biomarkers. Full article