Search Results (2,751)

Background/Objectives: Immune exclusion in head and neck squamous cell carcinoma (HNSCC) limits immunotherapy efficacy, yet the molecular determinants of stromal-immune organization remain incompletely characterized. The desmosomal cadherin DSG2 is highly expressed in squamous epithelium; its role in shaping the tumor microenvironment (TME) is unknown. Methods: We integrated bulk RNA-seq from 836 HNSCC patients (TCGA-HNSC n = 566, GSE65858 n = 270), single-cell RNA-seq (GSE139324, n = 26 patients, 133,308 cells), spatial transcriptomics (GSE208253, n = 12), proteomics (CPTAC-HNSCC, n = 108), and external validation cohorts (GSE41613, n = 97). CellChat ligand-receptor analysis, mediation analysis, Mendelian randomization (MR), LASSO-penalized Cox regression, HPV-stratified sensitivity analysis, and transcription factor (TF) correlation analysis were employed. Results: DSG2 exhibited epithelial-specific expression and showed consistent positive correlation with CXCL8 (IL-8; TCGA ρ = 0.228, p = 4.4 × 10⁻⁸) and myCAF activation across independent cohorts. Single-cell analysis revealed that 99.5% of CXCL8-producing cells have zero DSG2 expression, establishing the bulk correlation as compositional rather than cell-intrinsic. CellChat identified CXCL8-CXCR2 as the strongest tumor-stroma interaction in DSG2-high regions (probability = 0.821, 1.80-fold enrichment). Mediation analysis demonstrated 43.6% (95% CI [34.3–53.6%]) of DSG2’s tissue-level association with myCAF activation is mediated through CXCL8 (compositional mediation). Multi-instrument MR (IVW: Beta = −0.028, p = 0.028; I² = 0.0%) corroborated the compositional model. Protein-level validation in CPTAC-HNSCC confirmed DSG2-CD8A inverse correlation (Spearman ρ = −0.35, p = 2.2 × 10⁻⁴). Pan-squamous meta-analysis confirmed negative DSG2-cytolytic activity correlations (pooled ρ = −0.213, 95% CI [−0.296, −0.128], I² = 58.6%, 4 cohorts). DSG2 correlated with TIDE score (ρ = 0.176) and TGF-β exclusion subscore (ρ = 0.428). DepMap analysis identified CXCR2 inhibitor collateral sensitivity (ρ = −0.408, p < 0.0001). An eight-gene co-expression module was validated in two independent cohorts (GSE41613: HR = 3.09, p = 0.003; GSE65858: HR = 1.57, p = 0.032). Conclusions: DSG2 marks a stromal-immune organizational state characterized by CXCL8-CXCR2 paracrine signaling, myCAF activation, and immune exclusion, conserved across squamous malignancies. DSG2-high/PD-L1-high tumors (30.4% prevalence) exhibit the worst predicted ICI response and represent a candidate population for biomarker-selected CXCR2 inhibitor trials in combination with anti-PD-1 therapy. Full article

Background/Objectives: High-grade serous carcinoma (HGSC) represents the most frequent subtype of epithelial ovarian cancer (OC) and is associated with malignant ascitic fluid (MAF), which fosters a pro-inflammatory microenvironment that supports tumor progression. Given its rich cellular and soluble content, MAF offers a valuable window into tumor–host interactions and disease dynamics. This study examines the immune landscape of MAF samples from 22 newly diagnosed treatment-naïve HGSC patients. Methods: Immune cell phenotypes and cytokine profiles were analyzed via flow cytometry. Patients were stratified according to time to death or recurrence (TDR), using a six-month interval from diagnosis to either documented recurrence or disease-specific death as the cutoff: TDR < 6 months defined as the worse prognosis group, whereas TDR ≥ 6 months defined the better prognosis group. The expression of immune checkpoint molecules on T cells and the effects of PD-1 blockade with Pembrolizumab were also assessed. Results: Patients with worst prognosis exhibited a marked pro-inflammatory cytokine milieu, with elevated levels of TNFα, IL-1β, IL-23, and IFNγ. Concurrently, their CD4⁺ and CD8⁺ T cells displayed evidence of a functional exhaustion-associated phenotype, marked by heightened expression of the inhibitory receptors TIM-3, PD-1, and LAG-3. Notably, treatment with Pembrolizumab (a PD-1 checkpoint inhibitor) significantly enhance T cell effector function. Conclusions: These results underscore a potential immunotherapeutic approach in anti-tumor immunity among selected HGSC patients, presenting a compelling direction for advancing OC treatment. Full article

The effect of Corosolic acid (CA) on vascular tone and the possible mecha-nisms involved remain unclear. The SPF-grade male Sprague-Dawley rats (Animal Ethics Approval ID: USM/IACUC/2025/(155)(1406)) were used. The vasorelaxant effects of CA were evaluated in endothelium-intact and endothelium-denuded rings precontracted with phenylephrine (PE), and in endothelium-intact rings precontracted with KCl. Possible mechanisms were examined using L-NAME, ODQ, methylene blue, indomethacin, atropine, propranolol, and potassium channel blockers (glibenclamide, TEA, BaCl₂, and 4-AP). The effects of CA on voltage-operated calcium channels (VOCCs) and IP₃ receptor (IP₃R)-mediated sarcoplasmic reticulum calcium release were also assessed. CA concentration-dependently relaxed endothelium-intact aortic rings precontracted with PE (RMAX = 90.08 ± 7.33%; pD₂ = 4.21 ± 0.08). The relaxation response was markedly reduced after endothelial removal and in KCl-precontracted rings. EDRF pathway inhibitors (L-NAME, ODQ, methylene blue, and indomethacin) and GPCR-related antagonists (atropine and propranolol) attenuated CA-induced relaxation. Among potassium channel blockers, glibenclamide and TEA showed stronger inhibitory effects. CA did not significantly inhibit VOCC-mediated CaCl₂-induced contraction but partially reduced PE-induced contraction under calcium-free conditions. The mechanisms for CA treating hypertension may involve NO/cGMP signalling, COX-related prostanoid pathways, GPCR-related mechanisms, potassium channel modulation, and partial inhibition of IP₃R-mediated calcium release. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, but the comparative cardiac safety of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-containing regimens versus programmed cell death protein 1 (PD-1)-only regimens in real-world populations remains poorly characterized. We compared cardiac outcomes between melanoma patients exposed to CTLA-4 blockade (ipilimumab) and those treated with anti-PD-1 therapy alone (nivolumab or pembrolizumab) using a large multicenter electronic health record database. Methods: This retrospective cohort study used de-identified data from the TriNetX Research Network (111 US healthcare organizations). Adults with melanoma (ICD-10-CM C43) who received ipilimumab (CTLA-4 exposed) were compared with those who received nivolumab or pembrolizumab without ipilimumab (anti–PD-1 only); both groups were therefore treated with immune checkpoint inhibitors, isolating the effect of CTLA-4 exposure. Propensity score matching (1:1) balanced demographics, cardiovascular comorbidities, and baseline antiarrhythmic use. The primary outcome was a cardiac conduction disorder composite; outcomes were assessed at 1 and 3 years. Results: Of 7313 CTLA-4-exposed and 11,481 anti-PD-1-only patients, 6841 matched pairs were analyzed (all standardized mean differences <0.03). CTLA-4 exposure was associated with a significantly higher incidence of cardiac conduction disorders that was already present at 1 year (3.8% vs. 2.1%; RR 1.82; 95% CI 1.48–2.24; p < 0.001) and persisted at 3 years (5.1% vs. 3.7%; RR 1.36; 95% CI 1.16–1.60; p < 0.001). Atrioventricular block was higher at both 1 year (RR 2.10; 95% CI 1.59–2.78) and 3 years (RR 1.49; 95% CI 1.20–1.85), and complete heart block was markedly increased at 3 years (0.5% vs. 0.2%; RR 3.28; 95% CI 1.67–6.43; p < 0.001). Heart failure was modestly higher with CTLA-4 exposure at both timepoints (1-year RR 1.35; 3-year RR 1.17). Conclusions: Among melanoma patients treated with immune checkpoint inhibitors, CTLA-4-containing therapy is associated with a higher burden of cardiac conduction disorders, including a roughly three-fold excess of complete heart block, that is evident within the first year and sustained thereafter. Because the CTLA-4-exposed cohort comprised both ipilimumab monotherapy and nivolumab plus ipilimumab and the subgroup analyses localized the excess risk to the combination regimen, this association reflects CTLA-4-containing (predominantly combination) therapy rather than ipilimumab monotherapy in isolation. These findings support electrocardiographic surveillance beginning during, not only after, treatment for patients receiving CTLA-4-containing immunotherapy. Full article

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers. Full article

Immune checkpoint inhibitors targeting the PD-1 pathway have improved outcomes in advanced gastric cancer; however, substantial heterogeneity in treatment response remains. Current prediction strategies mainly rely on pretreatment biomarkers, which provide static assessments and may not capture the evolving interactions between tumor progression and host immunity. This study aimed to develop a dynamic prediction framework integrating longitudinal clinical trajectories and immune remodeling for continuous risk assessment during PD-1 inhibitor therapy. Methods: This retrospective study included 171 patients with gastric cancer receiving PD-1 inhibitor-based treatment. A landmark analysis framework was established using sequential 28-day follow-up windows to predict subsequent progressive disease (PD) or recurrence based on available clinical and immune information. Three nested models were developed: a baseline model (M0), a dynamic clinical model (M1), and an immune-integrated model (M2) incorporating longitudinal lymphocyte subset features. Model performance was evaluated using discrimination, calibration, and internal validation with patient-level resampling strategies. Results: Predictive performance improved progressively with incorporation of longitudinal information. The ROC AUC increased from 0.559 (95% CI, 0.429–0.690) in M0 to 0.737 (95% CI, 0.613–0.852) in M1 and 0.786 (95% CI, 0.681–0.883) in M2. Dynamic clinical information significantly improved discrimination compared with baseline prediction (ΔAUC = 0.178, p = 0.025), while additional immune features further enhanced risk stratification (ΔAUC = 0.049, p = 0.040). Interpretation analysis identified tumor burden evolution, neutrophil-to-lymphocyte ratio trajectories, and immune functional axes involving T-cell, innate cytotoxicity, and humoral immunity as major contributors to risk estimation. Landmark analyses demonstrated the feasibility of continuously updating PD/recurrence risk during treatment. Conclusions: This study establishes a dynamic landmark prediction framework integrating longitudinal clinical trajectories and immune remodeling for continuous risk assessment during PD-1 inhibitor therapy. Dynamic clinical and immune features provided complementary predictive information beyond baseline characteristics, supporting an adaptive approach for precision immunotherapy monitoring in gastric cancer. Full article

Glioblastoma (GBM) is one of the most aggressive and treatment-resistant cancers, shaped by a tumor microenvironment (TME) that is both metabolically demanding and strongly immunosuppressive. GBM relies heavily on fatty acid (FA) metabolism to sustain growth of rapidly dividing tumor cells and survive metabolic stress. GBM cells enhance lipid uptake, activate sterol regulatory element-binding protein 1 (SREBP-1)-driven lipogenesis, store excess lipids in droplets to prevent toxicity, and depend on fatty acid oxidation (FAO) to generate adenosine triphosphate (ATP) and maintain redox balance, particularly under nutrient-limited conditions. GBM TME is also consistently enriched with regulatory T cells (Tregs), which maintain suppressive activity despite the nutrient restrictions that impair effector T cells (Teffs). In hypoxia and nutrient limitation within the TME, Tregs can adapt by using FAO, lactate oxidation, and OXPHOS, supported by forkhead box P3 (Foxp3)-dependent metabolic programming, cluster of differentiation 36 (CD36)-mediated FA uptake, and hypoxia-related signals. At the same time, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling reduces glycolytic activity in Teffs and contributes to metabolic dysfunction, while also supporting the stability of oxidative metabolism in Tregs. Evidence from pre-clinical and clinical studies suggests a possible association between Treg enrichment in GBM and reduced responsiveness to immune checkpoint inhibitors (ICIs), although this relationship is not yet fully defined. Overall, current findings point to FA metabolism as a shared metabolic axis that supports both tumor progression and Treg-mediated immune resistance. Targeting lipid-driven pathways may offer an opportunity to disrupt these advantages and improve the effectiveness of existing immunotherapies for GBM. Full article

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy associated with rapid proliferation, early metastatic spread, and poor long-term survival. Despite high initial responsiveness to chemotherapy and radiotherapy, most patients experience relapse, and therapeutic progress historically remained limited. Recent years, however, have seen meaningful advances that are beginning to reshape the management of SCLC. In extensive-stage disease, the incorporation of PD-L1 inhibitors into platinum-etoposide chemotherapy has established chemoimmunotherapy as the first-line standard, while underscoring the continued need for more durable disease control. In limited-stage SCLC, consolidation durvalumab following concurrent chemoradiotherapy has emerged as a practice-changing strategy with significant survival benefit. In relapsed disease, DLL3-targeted therapy has opened a new therapeutic avenue, with tarlatamab demonstrating clinically relevant efficacy in previously treated extensive-stage SCLC and becoming the first approved bispecific T-cell engager in this setting. Alongside these milestones, ongoing investigation is focused on maintenance strategies, novel targeted agents, biomarker development, molecular subtyping, and more effective integration of systemic therapy with radiation-based approaches. Nevertheless, resistance, toxicity management, central nervous system involvement, and the absence of validated predictive biomarkers remain major barriers to sustained progress. This narrative review examines recent advances in the biology and clinical management of SCLC, with emphasis on practice-changing developments, emerging therapeutic platforms, and future strategies aimed at improving outcomes in this historically difficult-to-treat disease. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

Vitiligo is an autoimmune depigmenting disorder characterized by marked heterogeneity in therapeutic response, both between patients and among lesions within the same individual. While current therapies primarily target interferon-γ (IFN-γ)-driven inflammation, clinical outcomes remain variable and frequently incomplete, suggesting that additional lesion-specific biological factors contribute to repigmentation potential. In this narrative review, we propose the concept of repigmentation competence to describe the capacity of an individual lesion to achieve clinically meaningful repigmentation under therapy. We hypothesize that this competence emerges from the interaction of four interconnected biological axes: (i) cytokine network and immune memory, (ii) local immune regulation, (iii) regenerative capacity, and (iv) microenvironmental permissiveness. A targeted search of PubMed/MEDLINE and ClinicalTrials.gov up to March 2026 was conducted to identify translational studies, mechanistic models, and clinical trials relevant to these pathways. Evidence was synthesized thematically with emphasis on cytokine-mediated mechanisms and their interaction with regenerative and tissue-context processes. The IFN-γ/CXCL9/CXCL10 axis and tissue-resident memory T cells (TRM) represent the most clinically validated drivers of disease persistence, as demonstrated by the therapeutic efficacy of JAK inhibitors, although immune suppression alone often fails to achieve complete or durable repigmentation. In contrast, regulatory pathways involving PD-1/PD-L1 signaling, regulatory T cells (Tregs), IL-10, TGF-β, and IL-2–based strategies remain biologically compelling but only partially translated into effective therapies. Regenerative capacity has also emerged as an important determinant of treatment response, with growing evidence supporting the role of melanocyte stem cell niches, follicular regeneration, and Wnt/β-catenin signaling. Accordingly, regenerative approaches such as non-cultured epidermal cell suspension (NCES) are increasingly being integrated into combination therapeutic strategies. The lesional microenvironment remains the least therapeutically developed axis despite growing experimental evidence supporting its importance in melanocyte survival and migration. Collectively, these observations suggest that the variable efficacy of current therapies may reflect different combinations of lesion-specific biological constraints. The emerging benefit of combination strategies may therefore derive not simply from additive effects, but from the simultaneous engagement of multiple axes involved in repigmentation competence. Our review supports a shift from a predominantly drug-centered model toward a lesion-oriented framework integrating immune, regenerative, regulatory, and microenvironmental determinants of response. Full article

Parkinson’s disease (PD) is characterised by the pathological aggregation of α-synuclein (α-syn) into Lewy body inclusions, yet no disease-modifying therapy exists. To address this, we developed an integrated computational pipeline combining quantitative structure–activity relationship (QSAR) modelling, structure-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energy calculations to repurpose FDA-approved drugs as α-syn fibril inhibitors. Two complementary QSAR model families were trained on 501 α-syn binding affinity records from BindingDB: Morgan extended-connectivity fingerprint (ECFP4) classifiers and a frozen ChemBERTa-77M-MLM transformer encoder, each using Random Forest and Logistic Regression. The applicability domain (AD) was assessed using Morgan–Tanimoto similarity (Tc ≥ 0.40) and calibrated ChemBERTa cosine distance (θ ≤ 0.367). A three-stage funnel applying central nervous system (CNS) permeability filters, a consensus QSAR probability threshold (≥0.80), and AD gating reduced 2241 FDA-approved drugs to 205 candidates for AutoDock Vina 1.2.6 docking against two sites on the cryo-electron microscopy (cryo-EM) α-syn fibril structure, PDB 6SSX: the inter-protofilament cleft (Site 1) and the non-amyloid-beta component (NAC) groove (Site 2). The Morgan fingerprint models achieved an area under the receiver operating characteristic curve (AUROC) of up to 0.940 and a balanced accuracy of 0.810; the ChemBERTa models achieved an AUROC of 0.785 and a balanced accuracy of 0.728. Notably, ChemBERTa AD covered 76.8% of the FDA drugs versus only 5.5% for Morgan–Tanimoto, enabling broad-spectrum screening. The top docking candidates were Olaparib (−7.91 kcal/mol), Paliperidone (−7.75 kcal/mol), Niraparib (−7.18 kcal/mol), Dordaviprone (−7.06 kcal/mol), and Parecoxib (−6.89 kcal/mol). The MD simulations over 200 ns across three independent replicates confirmed stable NAC groove binding, and replicate-averaged MM-PBSA calculations yielded ΔG = −20.6 ± 1.9 kcal/mol for Olaparib at Site 2, −17.1 ± 0.9 kcal/mol for Risperidone, and −16.9 ± 0.8 kcal/mol for Paliperidone, reported as the mean ± standard error of the mean (SEM) across replicates. Olaparib additionally formed five hydrogen bonds in the representative pose, while MD trajectories maintained approximately 2–5 hydrogen bonds, together with a halogen bond within the NAC groove, the largest contact count of any screened compound. These findings identify Olaparib as a novel high-affinity repurposing lead, while Paliperidone and Risperidone are reported as chemically informative secondary NAC–groove binders rather than proposed antiparkinsonian therapeutics, given that their dopamine D2-antagonist pharmacology is clinically associated with drug-induced parkinsonism. All of the candidates warrant experimental validation via thioflavin-T fluorescence or nuclear magnetic resonance (NMR) spectroscopy. Full article

Background/Objectives: Covalent inhibitors often demonstrate prolonged pharmacological effects even after their disappearance from the site of action because target recovery depends on target turnover. This disconnect between pharmacokinetics (PK) and pharmacodynamics (PD) complicates the development of such inhibitors since plasma exposure coverage of in vitro potency cannot be used for compound selection and human dose projections. In this study, we describe the development of a PK/PD modeling framework for covalent inhibitors. Methods: The model was developed for KRAS G12C inhibitors using pre-clinical data on sotorasib. The model was validated using data from both internal Amgen compounds and published data for several KRAS G12C inhibitors. The applicability of the framework was extended to EGFR covalent inhibitors by incorporating PK/PD and the efficacy of osimertinib and its active metabolite AZ5104. Results: The model successfully captured the pharmacokinetics, KRAS G12C target occupancy, inhibition of phosphorylation of ERK protein, and tumor growth inhibition following the administration of sotorasib in mice bearing MIA PaCa-2 xenografts. External validation with several internal Amgen compounds as well as publicly available data on KRAS G12C inhibitors showed the robustness of the model. The application of this framework to EGFR inhibitor Osimertinib and AZ5104 captured p-EGFR dynamics and resultant tumor growth inhibition. Conclusions: A modeling framework for covalent inhibitors was developed that links exposure to target occupancy, downstream signaling, and tumor efficacy. This framework could be useful for compound optimization and human dose projections. Full article

Graves’ disease is an autoimmune hyperthyroid disorder in which thyroid peroxidase (TPO) plays a central role in excessive thyroid hormone production. However, current TPO-targeting drugs, such as propylthiouracil, have limited selectivity and can cause serious adverse effects. In this study, we established an integrated discovery pipeline to identify and optimize novel small-molecule TPO inhibitors. The pipeline began with high-throughput screening of approximately 7000 compounds from the KRICT chemical library for peroxidase inhibition, followed by cytotoxicity filtering and iterative medicinal chemistry to generate NE-2 derivatives. Lead compounds (NE-2-6, NE-2-7, and NE-2-8) were evaluated using enzymatic assays, selectivity profiling against myeloperoxidase (MPO) and lactoperoxidase (LPO), molecular docking, plasma pharmacokinetic profiling, and in vivo antithyroid pharmacodynamic testing in an Ad-TSHR289-induced thyroid hyperfunction model. NE-2-6 exhibited potent TPO inhibitory activity and relative selectivity within the tested peroxidase panel. UV–visible spectral scanning and H₂O₂-dependent inhibition assays suggested that NE-2-6 perturbs the heme-associated catalytic environment of TPO; however, these data do not establish a definitive binding mode or kinetic inhibition mechanism. In the Ad-TSHR289-induced thyroid hyperfunction model, NE-2-6 reduced serum T4 levels, supporting antithyroid pharmacodynamic activity. Because autoimmune endpoints and dose-matched PK–PD relationships were not fully assessed, the findings should be interpreted as preliminary preclinical evidence supporting further evaluation of NE-2-6 as a TPO-targeting antithyroid candidate. Full article

O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, and durable benefit from immune checkpoint inhibitors is limited by immune exclusion, microenvironmental immunosuppression, and toxicity. This narrative translational review evaluates whether endobronchial intratumoral delivery of immuno- and gene-based therapies can transform bronchoscopic access into a therapeutic platform linking local tumour intervention with systemic antitumour immunity. We synthesise evidence on endobronchial ultrasound, electromagnetic navigation bronchoscopy, and robotic-assisted bronchoscopy, together with local checkpoint blockade, cytokine and mRNA-lipid nanoparticle constructs, oncolytic virotherapy, dendritic-cell approaches, viral and non-viral gene transfer, and enzyme- or metabolite-based strategies. Current clinical evidence remains preliminary, consisting mainly of Phase I trials, small prospective cohorts, and case-based signals, with feasibility and safety observations but no completed randomised trial demonstrating efficacy against standard-of-care systemic therapy. The most plausible candidates are patients with advanced or recurrent NSCLC, bronchoscopically accessible lesions, inadequate response to systemic immunotherapy, and immune-excluded or locally immunosuppressed tumours. Biomarkers such as PD-L1, tumour mutational burden, CD8+ infiltration, tertiary lymphoid structures, radiomics, and circulating tumour DNA require validation. This review integrates delivery technology, immune mechanisms, statistical evidence appraisal, biomarker limitations, AI-guided planning, and global feasibility. Full article