Search Results (6,076)

Prostate cancer is the prototypical immunologically cold solid tumor, with objective response rates of only 3–5% to immune checkpoint inhibitors in unselected metastatic castration-resistant disease and an estimated 89.8% of tumors classified as immunologically ignorant. Three convergent features sustain this phenotype: low tumor mutational burden with defective Major Histocompatibility Complex class I antigen presentation; an immunosuppressive microenvironment dominated by regulatory T-cells, myeloid-derived suppressor cells, and M2 macrophages; and dense stromal and vascular barriers that exclude effector lymphocytes. Across these mechanisms, one compartment has received disproportionately little attention: the lymphatic system. Tumor-associated lymphatic remodeling driven by vascular endothelial growth factor C and D produces structurally abnormal vessels that impair antigen and dendritic cell trafficking to tumor-draining lymph nodes; the lymph nodes themselves are reprogrammed to a tolerogenic state by lymphatic endothelial cells expressing programmed death-ligand 1 and lacking costimulation and by regulatory T-cells that suppress effector egress. This review synthesizes evidence that in prostate cancer, immune coldness reflects not merely a problem of checkpoint engagement with the tumor but a failure of antigen trafficking at the lymphatic interface. We discuss therapeutic strategies that target this axis, such as lymphangiogenesis-inducing vaccines, lymph-node-directed checkpoint delivery, induction of intratumoral tertiary lymphoid structures and stromal reprogramming, as complements to existing immunotherapy. Targeting trafficking, not only checkpoints, may be the prerequisite for converting PCa from cold to hot. Full article

Background: Influenza remains a significant global public health threat, causing substantial morbidity and mortality worldwide. While vaccination serves as the best preventive strategy, considerable interindividual variability in vaccine-induced immune responses persists. The ZBTB46 rs2281929 polymorphism (c.A31G; p.T11A; ACG>GCG), which corresponds to the evolutionarily conserved mouse mutation Zbtb46^T11A (c.A31G; ACT>GCT), has been associated with enhanced antibody responses to influenza vaccination in humans, though its functional mechanisms remain unknown. This study aimed to investigate how this mutation affects influenza vaccine immunogenicity using a knock-in mouse model. Methods: A Zbtb46^T11A knock-in mouse model was generated using CRISPR/Cas9 technology. Homozygous (HO) and wild-type (WT) mice were immunized with a quadrivalent influenza vaccine in a prime-boost regimen. Humoral immune responses were assessed by Enzyme-linked immunosorbent assay, hemagglutination inhibition (HI), and microneutralization (MN) assays. Antibody-secreting cells (ASCs) were quantified by Enzyme-linked immunospot assays. Germinal center B cells, plasma cells, plasmablast cells, conventional dendritic cell (cDC) subsets, and T helper (Th) cells were analyzed by flow cytometry. Statistical comparisons were performed using a two-sample t-test. Results: The Zbtb46^T11A mutation did not alter Zbtb46 protein expression or its abundance in cDCs. Following vaccination, HO mice exhibited significantly enhanced humoral responses, including higher HA-specific IgG titers, HI and MN antibody levels, and increased numbers of ASCs. Flow cytometry revealed elevated proportions of germinal center B cells and plasma cells in HO mice. Furthermore, HO mice showed a selective expansion of type 1 cDCs (cDC1s) and a concomitant increase in Th1 cell frequencies and IFN-γ-secreting cells, while cDC2 proportions and Th2 responses remained unchanged. Conclusions: The Zbtb46^T11A mutation is associated with enhanced influenza vaccine immunogenicity, concomitant with increased cDC1 proportions, Th1 polarization, and germinal center-dependent humoral immunity. These observed associations suggest a candidate mechanism whereby Zbtb46 modulation may shape adaptive immunity, though further functional studies are required to establish causality. These findings provide insights into host genetic variation in vaccine responsiveness and may inform personalized vaccination strategies. Full article

Succinate is a metabolite involved in chronic inflammatory diseases, regulating macrophages, dendritic cells, and lymphocytes via its receptor SUCNR1 and through intracellular pathways. Our aim was to analyze whether the succinate–SUCNR1 axis modulates the leukocyte–endothelium interactions (L/EI) that mediate the formation of inflammatory foci in response to a ubiquitous pro-inflammatory cytokine (TNFα). L/EI were analyzed in murine cremasteric venules in vivo and between human umbilical endothelial cells (HUVECs) and peripheral blood mononuclear cells (PBMCs) in vitro. We observed that TNFα increased the expression of SUCNR1 and that the L/EI, the proinflammatory cytokines’ upregulation and the NF-κB activation that induced this cytokine were reduced in Sucnr1^−/− mice in comparison with WT mice. Intrascrotal injection of exogenous succinate did not induce significant proinflammatory effects per se but, combined with TNFα, allowed a Sucnr1-independent upregulation of pro-inflammatory cytokines. In vitro, the SUCNR1 antagonist NF-56-EJ40 prevented the interactions of PBMCs with TNFα-treated HUVECs. HUVECs incubated with exogenous succinate presented higher L/EI but a limited response to TNFα. SUCNR1 contributes to TNFα-induced leukocyte–endothelial interactions. However, exogenous administration of high concentrations of this succinate exerts a complex pattern of effects that may include anti-inflammatory actions. Full article

In this study, Se-excess Ge₂Sb₂SeₓTe₁ (GSST) thin films were synthesized via magnetron co-sputtering. The crystal structure, surface morphology, complex refractive index, and bandgap of the Se-excess GSST thin films were systematically investigated. Owing to the formation of higher-energy Sb–Se bonds at an annealing temperature of 350 °C, grain refinement occurred (the average dendrite trunk width decreased from 0.64 μm to 0.37 μm). Consequently, the extinction coefficient (k) in the crystalline state was reduced to 0.17, resulting in a figure of merit (FOM) of 8.76 at the telecommunications C-band wavelength of 1550 nm. Full article

Background/Objectives: Sjögren’s Syndrome (SS) is an autoimmune disorder with impaired exocrine gland function. Its pathogenesis remains elusive, but aberrant innate/adaptive immunity and dysregulated interferon signaling are core features. Current SS research lacks exploration of innate immune mechanisms and therapeutic targets. Phloretin, a natural dihydrochalcone derivative, inhibits excessive innate immune activation, yet its role and mechanism in SS remain unreported. Methods: This study aimed to explore the therapeutic efficacy of phloretin against Sjögren’s syndrome (SS) and elucidate the regulatory mechanism underlying its effects on dendritic cells (DCs) and the Stimulator of Interferon Genes (STING)-driven innate immune cascade. Clinical specimens were utilized to analyze DC infiltration and STING expression in the labial glands of SS patients. In vivo experiments were conducted on NOD/Ltj SS mice with phloretin treatment, using hydroxychloroquine as a positive control. For in vitro studies, DCs were stimulated with poly I:C to verify the functional effects of phloretin and its regulatory role in the STING/TANK-binding kinase 1 (TBK1)/Interferon Regulatory Factor 3 (IRF3) signaling. Salivary secretion, glandular inflammatory responses, and systemic immune overactivation were evaluated in SS mice. In poly I:C-stimulated DCs, cell activation, migration, and co-stimulatory molecule expression were measured. The regulatory effects of phloretin on the STING signaling cascade and STING ubiquitin-mediated degradation were examined by Western blotting. Phloretin, initially identified as a candidate compound via virtual screening, was subjected to thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulation (MD) for direct binding verification with STING. The STING overexpression rescue experiment further corroborates that phloretin modulates innate immune responses in a STING-dependent manner. Results: Clinical results revealed obvious infiltration of CD11c⁺STING⁺ DCs and CD11c⁺p-TBK1⁺ DCs in labial gland lesions of SS patients. In NOD/Ltj SS mice, phloretin treatment recovered salivary secretion, relieved glandular inflammatory injury, and restrained excessive activation of innate and adaptive immune responses, showing comparable therapeutic effects compared with hydroxychloroquine. In vitro experiments confirmed that phloretin could alleviate poly I:C-induced abnormal activation and migration of DCs, as well as reduce the expression of co-stimulatory molecules. Mechanistically, phloretin was found to interfere with the STING signaling cascade, alter the ubiquitination level of STING protein, and further inhibit the abnormal activation of DCs, which may contribute to its protective effects against Sjögren’s syndrome. Notably, results from MD, CETSA and DARTS collectively validate the interaction between phloretin and STING protein, providing solid molecular-level evidence for its regulatory effect on STING signaling transduction. Conclusions: DCs and STING-driven innate immunity critically contribute to SS progression. Phloretin effectively ameliorates SS-related immune disorders by restraining DC overactivation and STING signaling, supporting it as a promising candidate agent for SS treatment. Full article

High-intensity interval training (HIIT) is widely recognized as an effective strategy for improving cardiorespiratory fitness and metabolic health. Beyond these physiological benefits, growing evidence indicates that HIIT may also induce beneficial immunometabolic adaptations. A key exercise-responsive metabolite in this context is lactate, which is increasingly being recognized not as a metabolic waste product but as a bioactive signaling metabolite capable of coordinating metabolic, inflammatory, and immune processes. This narrative review examines current evidence suggesting a potential role for exercise-induced lactate in immune responses associated with HIIT. We summarize the molecular pathways through which lactate may interact with immune cells, including uptake via monocarboxylate transporters (MCT1/MCT4) and SLC5A12, receptor-dependent signaling through GPR81/HCAR1, and epigenetic regulation via histone lactylation. We further discuss the cell-specific effects of lactate on macrophages, dendritic cells, neutrophils, and T lymphocytes, highlighting how these mechanisms may influence immune-cell metabolism, inflammatory regulation, and functional remodeling. A central concept emerging from the current literature is that the biological actions of lactate are highly dependent on the kinetics, duration, and physiological context of exposure. Unlike pathological lactate elevations observed in conditions such as cancer, sepsis, or mitochondrial myopathies—the latter potentially involving an exaggerated lactate response during exercise due to impaired oxidative metabolism—HIIT generates transient systemic lactate elevations as part of a coordinated neuroendocrine and metabolic response. When combined with adequate recovery, these repeated metabolic perturbations may promote hormetic adaptations characterized by improved inflammatory regulation, enhanced immune resilience, and more efficient immunometabolic homeostasis. Conversely, excessive training loads or inadequate recovery may shift these responses toward maladaptive immune stress. Overall, current evidence suggests a paradigm shift in exercise immunology in which lactate should be regarded as one component of an integrated immunometabolic signaling network rather than simply as a marker of anaerobic metabolism. Future mechanistic studies integrating lactate kinetics, immune-cell phenotyping, transporter expression, and lactate-dependent post-translational modifications are needed to clarify the extent to which lactate may contribute to exercise-induced immune remodeling and to guide the development of immunologically informed HIIT protocols. Full article

Objectives: Nasopharyngeal carcinoma (NPC) arises in an immune-suppressive milieu that frequently undermines treatment efficacy. TPPP3 has been implicated as a negative regulator of NPC aggressiveness, yet its relevance to immune modulation or chaperone networks remains poorly defined. We therefore sought to determine how TPPP3 shapes the NPC immune landscape and to identify its interacting protein partners. Methods: Public single-cell RNA-sequencing datasets from head and neck squamous cell carcinoma and nasopharyngeal carcinoma were analyzed using R. HK-1 and C666-1 cells stably overexpressing TPPP3 were established. These cells were used to construct humanized xenograft tumor models, with intratumoral immune cell infiltration evaluated by immunohistochemistry. In vitro, the same cells and their controls were indirectly co-cultured with peripheral blood mononuclear cells. Cellular lysates from TPPP3-overexpressing cells were subjected to immunoprecipitation–mass spectrometry and immunofluorescence staining, which identified HSPA8 as a TPPP3-interacting protein. Three groups—control, TPPP3-overexpressing, and TPPP3-overexpressing plus the HSPA8 inhibitor VER155008—were then compared in wound healing, colony formation, cell-cycle, and xenograft assays, with immunohistochemical staining for Ki67, TPPP3, and CD3 performed on tumor sections. Results: TPPP3 transcripts were barely detectable across most tumor cell subsets but showed preferential enrichment in NPC epithelial clusters. Enforced TPPP3 expression curtailed xenograft outgrowth while increasing intratumoral abundance of CD3⁺ T cells, CD8⁺ T cells, and CD11c⁺ dendritic cells. Pharmacological blockade of HSPA8 with VER155008 further enhanced TPPP3-driven suppression of migration, clonogenicity, and tumor expansion, and also altered cell-cycle progression while boosting CD3⁺ T-cell accumulation within grafts. Conclusions: These findings suggest a functional association between TPPP3 and HSPA8 that may contribute to tumor growth suppression and immune microenvironment remodeling in NPC. Pharmacological disruption of HSPA8-dependent proteostasis enhanced TPPP3-associated antitumor activity in both in vitro and in vivo models, indicating that this chaperone pathway represents a candidate mechanism worthy of further mechanistic investigation and therapeutic exploration. Full article

Magnetic field-assisted casting technologies have received extensive research attention. Applying a transverse magnetic field during directional solidification offers an effective, non-contact approach to control the microstructure of Cu-Ag alloys by modulating melt convection. However, a comprehensive quantitative understanding of its mesoscopic influence on solute-driven dendritic growth and the columnar-to-equiaxed transition (CET) is still lacking. In this study, a coupled phase-field and lattice Boltzmann (PF-LBM) model is employed to systematically investigate the effect of a transverse magnetic field on columnar dendrite evolution and CET kinetics during the directional solidification of Cu-Ag alloys. Results show that the field-induced Lorentz force disrupts the symmetry of the solute field ahead of the dendrite tip, driving tilted dendritic growth that intensifies with decreasing initial primary spacing. During the CET process, the magnetic field overrides the randomness of grain nucleation by selecting specific crystallographic orientations. More importantly, it effectively mitigates the thermodynamic suppression of equiaxed nucleation typically caused by high temperature gradients. Furthermore, an increased magnetic field intensity not only accelerates the occurrence of CET but also significantly diminishes the inhibitory effect of high nucleation barriers on the transition. Ultimately, this work provides fundamental insights into external field-induced orientation selection mechanisms of as-cast grains and establishes a theoretical framework for quantitatively controlling texture evolution during the subsequent processing of high-flexure Cu-Ag alloys. Full article

Titanium dioxide, a traditional physical sunscreen agent, has long faced persistent challenges related to light transmission (manifesting as whitening and an unnatural white cast on the skin), high photocatalytic activity, and cytocompatibility concerns. In this work, a composite sunscreen material, mesoporous silica (MSN)@TiO₂, was designed and synthesized by loading titanium dioxide (TiO₂) onto dendritic mesoporous silica. Leveraging the high transparency of dendritic mesoporous silica, MSN@TiO₂ exhibits 30% higher visible light transmittance than commercially available titanium dioxide. In addition, encapsulation within the silica carrier reduces the photocatalytic activity of MSN@TiO₂ to one-seventh of that of commercially available titanium dioxide. Furthermore, we evaluated the cytocompatibility of MSN@TiO₂. Cell Counting Kit-8 (CCK-8) assay results demonstrate that MSN@TiO₂ has a less pronounced effect on L929 cells proliferation compared with commercial TiO₂, indicating favorable L929 cell-based cytocompatibility. This strategy demonstrates that MSN@TiO₂ combines a natural appearance with low photocatalytic activity, offering distinct advantages over conventional titanium dioxide in composite sunscreen materials. Full article

Background/Objectives: Psoriasis is a chronic inflammatory skin disease driven by Th17/Treg imbalance. Colquhounia Root Tablet (CRT), derived from Tripterygium hypoglaucum, has shown clinical potential for psoriasis, but its mechanisms remain unclear. This study aimed to evaluate the anti-psoriatic effects of CRT and elucidate its underlying mechanisms. Methods: Anti-psoriatic activity was evaluated in an IMQ-induced psoriasis-like mouse model. Mice received oral CRT at 0.085, 0.17, or 0.35 g/kg daily from days 2 to 8. Immune-cell populations were analyzed by flow cytometry. Bone marrow-derived dendritic cells (BMDCs) were used for in vitro studies. Network pharmacology, transcriptomics, molecular docking, and experimental validation were integrated to explore the mechanisms. Results: CRT dose-dependently ameliorated psoriasiform dermatitis and reduced Th17/Treg ratio while inhibiting CD11c⁺MHC II⁺ DC activation in vivo. In vitro, CRT suppressed R848-induced BMDC maturation and inhibited p65/IκBα phosphorylation. Transcriptomic analysis revealed modulation of TNF, NF-κB, IL-17, and JAK-STAT pathways. Molecular docking predicted the strong binding of multiple CRT compounds to RELA. Conclusions: CRT exerts anti-psoriatic effects in a murine model with concurrent modulation of NF-κB-related DC maturation and Th17/Treg correction, suggesting a potential immunomodulatory mechanism requiring further causal validation. Full article

Cancer immunotherapy faces significant challenges in treating “cold” tumors, which respond poorly to current strategies. Breast cancer is a major cause of cancer-related mortality in women and is a representative immunosuppressive cold tumor. The luminal A subtype of breast cancer exhibits an immune-cold phenotype, with MCF-7 cells used as a representative cell model. Here, we identified (3β,5α,8α)-5,8-epidioxyergost-6-en-3β-ol (EEO), isolated from Gymnopilus orientispectabilis, as an inducer of immunogenic cell death (ICD) hallmarks in MCF-7 cells, including cell surface exposure of calreticulin (CRT) and the extracellular release of damage-associated molecular patterns (DAMPs), such as ATP and High Mobility Group Box 1 (HMGB1). These ICD-associated events subsequently promoted CRT-dependent dendritic cell (DC) activation in a co-culture system with bone marrow-derived DCs and MCF-7 cells. Furthermore, surface-exposed CRT enhanced the phagocytosis of EEO-treated MCF-7 cells by DCs, and this phagocytic activity promoted DC maturation, as indicated by increased cell surface levels of the maturation markers major histocompatibility complex class II (MHC II) and cluster of differentiation 86 (CD86). Moreover, CRT knockdown in MCF-7 cells reduced surface CRT exposure following EEO treatment, thereby suppressing DC-mediated phagocytosis and subsequent DC maturation. Taken together, these findings suggest that EEO is a promising candidate for enhancing the antitumor efficacy of existing breast cancer immunotherapies through ICD-mediated DC maturation and converting immunologically cold tumors into hot tumors. Full article

Sulfide solid electrolytes (SSEs) are promising for all-solid-state lithium batteries (ASSLBs) due to their high ionic conductivity, mechanical deformability, and interfacial compatibility. However, SSE interfaces with anodes, cathodes, conductive additives, and current collectors are unstable, triggering safety failures like capacity degradation, internal resistance build-up, thermal runaway, and short circuits. This review summarizes recent progress on interface-induced safety failure mechanisms in sulfide-based ASSLBs, focusing on interface types, failure mechanisms, and thermal/mechanical degradation under multi-field coupling. We survey interface modification strategies and highlight advanced characterization techniques for probing interfacial phenomena. Key challenges and future research directions are discussed. Integrating recent findings, we identify interfacial instability as the primary bottleneck governing safety failures, providing a theoretical and technical framework for rational interface design, performance optimization, and safety enhancement. Throughout this review, we use SSE as the standard abbreviation for sulfide solid electrolytes. Full article

Nipah virus (NiV) is a single-stranded negative-sense RNA virus of the genus Henipavirus, family Paramyxoviridae. The World Health Organization has declared NiV a priority pathogen with a great public health risk due to its epidemic potential and lack of sufficient countermeasures. In humans, the virus causes Nipah viral disease (NVD), characterized by acute respiratory failure and/or encephalitis. Long-term assessments of NVD survivors have revealed persistent neurological dysfunction, including encephalopathy, cerebral atrophy, hyperintensities, ocular motor palsies, and dystonia. The entry of NiV into the central nervous system (CNS) is one of the critical and less studied aspects of its pathogenesis. NiV rapidly targets the olfactory epithelial cells in the nasal turbinate and subsequently infects neurons, allowing its spread into the CNS via axonal transport. In addition, infection of immature dendritic cells has been associated with severe CNS disease, supporting a potential role of hematogenous dissemination in neuroinvasion. Overall, understanding the molecular mechanism and the role of host factors in NiV neuropathogenesis is crucial for developing effective strategies to combat NVD. The present review delves into the neuropathogenic mechanism and immunobiology of NiV infection, as well as advancements in therapeutic modalities and vaccines against NVD. Full article

Laser powder bed fusion enables the fabrication of complex Inconel 718 components, but rapid solidification produces pronounced microsegregation that complicates subsequent phase evolution. In this study, scanning electron microscopy, transmission electron microscopy, and energy dispersive spectroscopy were combined with JMatPro calculations to examine as-built microsegregation and phase behavior in laser powder bed-fused Inconel 718. The as-built alloy exhibited a continuous cellular and dendritic substructure, a high dislocation density, and interdendritic constituents with pronounced Nb enrichment and weaker local Mo enrichment. Equilibrium calculations based on the measured powder composition predicted γ formation at approximately 1350 °C and a liquid plus γ region between 1195 and 1350 °C. The calculated stability ranges of MC, δ, η, γ′, σ, M₂₃C₆, Laves, and μ phases were also identified. Comparison with the experimental observations showed that calculations using the nominal composition cannot directly represent the strongly segregated interdendritic regions formed during rapid solidification. The TTT and CCT calculations indicated that δ phase precipitation is most sensitive at approximately 900 to 1000 °C. The results clarify the distinction between local nonequilibrium phase formation and bulk phase stability and highlight the role of Nb redistribution among interdendritic constituents, the δ phase, and γ″ and γ′ precipitates. The calculated results should be regarded as a qualitative reference. Further local composition-based calculations and experimental validation are required before they can be applied to heat treatment design. Full article

Background/Objectives: Osteosarcoma (OS) is an aggressive bone malignancy with a complex tumor microenvironment (TME) that influences therapeutic outcomes and resistance. How neoadjuvant chemotherapy (NACT) reshapes the OS TME at single-cell resolution remains largely undefined. This study aimed to characterize cellular heterogeneity in the OS TME after NACT and identify chemokine-mediated intercellular crosstalk driving chemoresistance. Methods: Single-cell RNA sequencing was performed on surgical specimens from 12 OS patients (6 treatment-naive and 6 post-NACT). After quality control, 77,616 cells (36,214 from naive patients, 41,402 from post-NACT samples) were analyzed through the Seurat pipeline. Unsupervised clustering, differential expression analysis, and cell–cell communication network construction were performed, and candidate signaling axes were validated using transwell assays and Western blotting. Results: Cells were classified into 10 major cell types. Osteoblasts, identified as malignant cells, were partitioned into 11 subpopulations with marked transcriptional heterogeneity and differential PI3K/Akt pathway activity. Post-NACT, stromal and vascular components underwent molecular and functional remodeling, shaping an immune-activated microenvironment. Mononuclear phagocytes resolved into three discrete clusters—monocytes, macrophages, and dendritic cells—with differentiation gradients. Endothelial cells maintained robust CXCL2 expression throughout the therapeutic course. Functional validation via transwell assays and Western blotting confirmed that endothelial-derived CXCL2 promoted macrophage chemotaxis via CXCR2, with corresponding CXCR2 upregulation in macrophages. Conclusions: Collectively, these findings suggest the complex cellular and transcriptional heterogeneity of the OS microenvironment and its chemokine-driven molecular remodeling after NACT, indicating that TME dynamics may be a determinant of therapeutic response and chemoresistance. Full article