Dissecting placental host-pathogen interactions: Rift Valley fever virus infection in early human trophoblast stem cells.

Matrine inhibits SGIV infection via regulation of the inflammatory and oxidative stress response.

Immune checkpoint blockade (ICB) therapy for many cancers remains limited in patients' overall response rate. Discovery and development of more effective combinatorial approaches is urgent. Here, through CRISPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress tumor-intrinsic immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type I interferon (IFN) response, and meanwhile lowers ZEB1 levels to further unleash the expression of immune-related genes. In turn, we demonstrate that DOT1L loss or treatment with the clinical stage inhibitor EPZ-5676 sensitizes tumors to ICB with increased immune infiltration in mice. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mice. TCGA data analysis reveals an inverse correlation between DOT1L expression and IFN signatures across multiple cancer types. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.

Sonodynamic therapy (SDT) offers deep tissue penetration and noninvasive tumor treatment, yet its efficacy remains limited by inadequate reactive oxygen species (ROS) generation and an immunosuppressive tumor microenvironment (TME). In this work, we developed a porphyrin-based bimetallic nanoplatform by integrating Fe and Mn centers within a structurally ordered metal-organic framework (MOF), followed by surface modification with the tumor-homing peptide CRGDK to achieve active targeting. The rationally engineered Mn-Fe(TCPP) MOF exhibits a spatially confined configuration that minimizes π-π aggregation of porphyrins enhancing ROS production under ultrasound (US). Meanwhile, Fe3+ and Mn2+ are released in the mildly acidic TME. The Fe3+ catalyzes Fenton-like reactions to generate abundant •OH radicals, leading to glutathione (GSH) depletion, glutathione peroxidase-4 (GPX4) inhibition, and triggers ferroptosis. Simultaneously, Mn2+ and ROS inflict mitochondrial damage and cause cytosolic double-stranded DNA (dsDNA) leakage, thereby activating the cGAS-STING signaling pathway and amplifying type I interferon (IFN-I) responses. This dual immunometabolic modulation induces immunogenic cell death (ICD), promotes dendritic cells (DCs) maturation, and strengthens adaptive antitumor immunity. Overall, this study presents a concise strategy coupling ferroptosis induction with innate-immune activation through a porphyrinic bimetallic MOF, offering a promising direction for SDT-based immunotherapy against hard-to-treat tumors.

Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infants, older adults, and immunocompromised individuals. A hallmark of RSV pathogenesis is early innate immune evasion by the nonstructural proteins NS1 and NS2. NS2 is a multifunctional interferon (IFN) antagonist that dampens both IFNβ induction and type I IFN responsiveness by targeting multiple nodes of the RIG-I/IFN signaling axis. Because NS2-mediated inhibition is often partial and context dependent, quantifying its effects in conventional cell-based assays is challenging. Here, we report the generation and characterization of a stable, virus-free reporter system in human A549 cells to measure NS2-dependent inhibition of dsRNA-driven IFNB induction. The platform combines stable NS2 expression with genomic integration of a dual cassette encoding a non-targeting short hairpin RNA that constitutively activates IRF-3 to induce a luciferase reporter under IFNB promoter control. This configuration yields a sensitive, reproducible luminescence readout of IFNB promoter activity in controlled, infection-free conditions, enabling robust quantification of NS2 antagonism with reduced variability. The scalable luminescence-based format supports early-stage discovery and prioritization of inhibitors that counteract NS2 function, and the modular design is adaptable to other viral antagonists, pathways, and cell types for standardized comparative studies.

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.

PARP14 as a Master regulator of immune signaling and tumor microenvironment remodeling.

Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease stages, particularly CD8⁺ T-cells that clustered around Aβ plaques, suggesting a targeted immune response. Among these, we identified an Aβ plaque-associated subset of CD8⁺ T cells expressing interferon-stimulated genes (ISGs), which promoted Type-I interferon signaling. This subset also produced CXCL10, facilitating the recruitment of non-ISG T cells through the CXCL10-CXCR3 axis. Importantly, similar Type-I interferon responses were detected near plaques in human CNS amyloid pathology. Together, these findings highlight a shift from microglia-driven to T-cell-mediated neuroinflammation as amyloid pathology progresses, with implications for time-resolved therapy development.

Defective interfering particles (DIPs) are incomplete viral genomes that modulate infection by competing with wild-type viruses and activating the innate immune response. Activation of the immune response leads to the production of cytokines and chemokines, including type I interferon (IFN), which restricts viral growth and may cause cell death. How DIPs interact with type I interferon (IFN) in spatially structured environments remains unclear. Focusing here on influenza A viruses, we developed a spatially explicit, stochastic model of in vitro viral infection that integrates virus and DIP replication, IFN signalling, and alternative dispersal modes. We find that: (1) our model captures the ring-like and patchy plaque morphologies observed experimentally; (2) IFN production peaks at an intermediate DIP ratio, reflecting a trade-off between early immune activation and sufficient co-infection; and (3) even a small fraction of long-range spread by virus and DIPs enables escape from the immune-based containment despite long-range IFN diffusion; this causes stronger antiviral responses but earlier peaks in virus egress at similar levels of cell loss. The model is available as an interactive platform: https://shiny-spatial-infection-app-production.up.railway.app/.

Endometrial cancer (ECa) is one of the most common gynecologic malignancies, with limited therapeutic responses in metastatic or recurrent cases. The bacterial microbiota has emerged as a key modulator of carcinogenesis and antitumor immunity. However, the role of endometrial microbiota in ECa pathogenesis and prognosis remains poorly understood. We performed comprehensive multi-omics analysis integrating metatranscriptomics, transcriptomics, and targeted metabolomics from 60 ECa and 18 benign patients. RNA sequencing enabled simultaneous profiling of active tissue-resident microbiota and host gene expression. Serum metabolomics was conducted on all patients. Identified microbial-metabolite associations were validated through in vitro co-culture experiments using peripheral blood mononuclear cells (PBMCs), cancer cell lines, RNA sequencing, and live cell imaging. ECa patients exhibited significantly altered microbial diversity and composition compared to benign controls. Through integrated multi-omics analysis, we identified Bacillus megaterium (BM) KCTC 3007 as a beneficial microbe associated with prolonged recurrence-free survival. In an exploratory analysis of ECa subtypes, Cupriavidus taiwanensis and Marinomonas primoryensis showed potential links to poor prognosis, although these observations warrant caution due to the limited size of certain subgroups. Tissue BM abundance positively correlated with serum trimethylamine N-oxide (TMAO) levels, particularly in postmenopausal women. In vitro experiments demonstrated that BM KCTC 3007 enhanced antitumor immunity by promoting interleukin and type I interferon expression, expanding CD8 + T cell populations, and increasing immune cell-tumor cell interactions. RNA sequencing revealed activation of interferon alpha response and immune cell proliferation pathways, with IFNAR1 identified as a key upstream regulator. TMAO treatment recapitulated these immune-activating effects, enhancing CD8 + T cell responses and preferentially inducing pyroptotic cancer cell death. We provide the first evidence that tissue-resident BM KCTC 3007 promotes antitumor immunity in ECa through TMAO production and subsequent type I interferon-mediated immune activation. This integrated multi-omics approach establishes a complete microbe-metabolite-host mechanistic pathway and highlights the therapeutic potential of TMAO-producing probiotic strains for ECa treatment. Video Abstract.

Respiratory syncytial virus (RSV) and influenza A virus (IAV) interplay with the type I and III interferon (IFN) responses in the respiratory epithelium.

Dendritic cells (DCs) integrate innate immune sensing with adaptive immune priming through coordinated transcriptional programs that regulate antiviral defense, inflammatory signaling, and antigen presentation. However, the hierarchical organization and interdependence of these pathways following stimulation remain incompletely defined. Here, we performed an in silico re-analysis with full reproducibility of publicly available RNA-sequencing data (GSE108526) to characterize the temporal architecture and associations of immune transcriptional modules in human dendritic cells at 6 h and 16 h following innate immune activation. Principal component analysis revealed stimulation status as the dominant source of transcriptomic variance. Differential expression analysis confirmed robust induction of interferon-stimulated genes (ISGs) alongside modulation of inflammatory mediators and antigen presentation-associated genes. Module-level quantification showed that interferon signaling constituted the primary early transcriptional axis, whereas inflammatory cytokine programs displayed moderate induction and antigen presentation-associated genes exhibited distinct temporal dynamics. Association analysis demonstrated strong relationships between CIITA and downstream MHC class II genes, supporting coordinated antigen presentation regulation, while relationships between interferon and inflammatory modules were positive but non-proportional, indicating partial modular independence. Collectively, these findings reveal a structured yet non-uniform transcriptional organization in stimulated human dendritic cells, characterized by dominant interferon responses accompanied by context-dependent inflammatory activation and differentially associated antigen presentation programs. This integrative framework provides a reproducible systems-level approach for dissecting immune transcriptional architecture in human dendritic cell activation.

Membrane lipids regulate the STING pathway and type I interferon responses.

Aberrant activation of the NLRP3 inflammasome contributes to a wide range of chronic inflammatory disorders. Here, we investigate small-molecule inhibitors originally developed to target the DNA repair enzyme hOGG1 and demonstrate their ability to inhibit NLRP3 activation in human cells. These compounds, including TH5487 (IC50 1.62 µM in human PBMCs), reduce IL-1β secretion while increasing type I interferon responses. Cryo-EM reveals direct association between NLRP3 and mitochondrial DNA, while structural modeling predicts interaction with oxDNA. Notably, inhibitors of the DNA repair glycosylase hOGG1 remain effective in L353P mutant PBMCs from FCAS patients and L351P in mice, at doses where the canonical NLRP3 inhibitor MCC950 is ineffective. Our findings uncover an additional druggable mechanism for inflammasome regulation via interference with oxidized DNA sensing, offering innovative therapeutic opportunities for autoinflammatory disease.

Organoid-based modeling unveils Dnmt3a-driven epigenetic regulation of phenotypic plasticity in small cell lung cancer.

Manganese-based metal-organic frameworks augment postoperative immunotherapy of high-intensity focused ultrasound.

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed significant challenges in understanding host antiviral immune responses. Among these, interferons (IFNs) play a critical role as the first line of defence against viral infections. IFNs are classified into three major types: type I, type II and type III, each contributing to antiviral immunity by activating interferon-stimulated genes that inhibit viral replication. This review aims to summarise current evidence regarding the role of interferons in SARS-CoV-2 infection, with a particular focus on airway epithelial cell models. These models are especially valuable as they closely mimic the structural and functional characteristics of the human respiratory epithelium, including the expression of Angiotensin-Converting Enzyme 2 (ACE2) receptors, thereby providing a physiologically relevant platform for studying viral entry, replication and host immune responses. A comprehensive literature search was conducted on 15 July 2025 using databases and keywords including “airway epithelial cells,” “SARS-CoV-2,” “COVID-19,” and “interferon.” A total of 86 articles were identified, of which 53 were included based on predefined relevance criteria, including studies focusing on interferon responses in airway epithelial models, experimental or clinical relevance to SARS-CoV-2 infection and availability of full-text articles in English. The findings indicate that interferon responses vary depending on cell type, viral variants and host factors such as age and environmental exposure. In conclusion, interferons play a pivotal role in the pathogenesis and potential treatment of COVID-19. Airway epithelial cell models remain essential tools for elucidating these mechanisms and for developing targeted antiviral therapies.

Tick-borne orthoflaviviruses (TBOVs) are spreading in various parts of the world, like Europe, Asia, and North America, making it essential to understand how they cause disease and how the immune system responds to infection. In vertebrates, the interferon (IFN) response is a key early defense against viruses, triggering the expression of numerous IFN-stimulated genes (ISGs) with antiviral activities. Using mouse models, we demonstrated the central role of IFNs in controlling TBOV replication. To explore this further, we screened for the activity of about 2,000 individual ISGs against tick-borne encephalitis virus (TBEV) in human cells and identified IFI6 as a potent antiviral factor. Through functional studies, virological assays, biochemical analyses, and microscopic approaches, we confirmed that IFI6 limits the replication of TBOVs. These findings enhance our understanding of innate immunity against TBOV infections.

Immune activation within tumors is governed by highly dynamic redox and mitochondrial signaling events, yet the temporal organization of these processes remains poorly defined. Here, we report a programmable DNAzyme nanocatalyst (APTZ) that enables time-dependent redox-immune coupling by translating intracellular catalytic activity into a transient biochemical signal window. The APTZ platform integrates ZnO nanoparticles, a catalase-targeting DNAzyme, and a tumor-homing aptamer, allowing acid-triggered Zn2+ release to induce sequence-specific catalytic cleavage of catalase mRNA. This reaction amplifies intracellular reactive oxygen species while depleting glutathione, leading to mitochondrial membrane depolarization, energetic collapse, and cytosolic release of mitochondrial DNA. The resulting mtDNA leakage activates the cGAS-STING pathway and induces a robust type I interferon response, thereby establishing a transient 4-6h redox sensitization window. Leveraging this temporally confined state enhances dendritic-cell maturation and cytotoxic T-cell infiltration when immune checkpoint blockade is applied within the defined window. Conceptually, this work demonstrates that programmable DNAzyme catalysis can be harnessed to generate actionable temporal biochemical cues, providing a nanobiotechnology framework for time-guided innate immune modulation and highlighting the broader potential of DNAzyme-based nanocatalysts in dynamic cancer immunotherapy .

Introduction Type I interferon response, specifically, the cGAS-cGAMP-STING axis that results in IFN-β response, is well known for its complex roles early during viral infection. Previous reports suggest that HSV-1 DNA in Thp-1 cells and HIV-2 dsDNA in DCs and macrophages could be sensed by cGAS. The nuclear DNA sensor IFI16’s viral DNA sensing leads to its acetylation, cytoplasmic translocation and STING activation and inflammasome activation. Although cGAS is known to be associated with IFI16 in the nucleus, however, during HSV-2 infection, the role of nuclear cGAS in viral DNA sensing, inflammasome formation and type I IFN response remains unknown. Methods In the current study, extensive investigation of the complex IFN-β responses elicited early during de novo HSV-2 infections in HFF cells is undertaken. The SiIFI16 and SicGAS treated HFF cells infected with HSV-2 demonstrate that cGAS senses nuclear herpes-viral DNA in an IFI16 dependent manner leading to nuclear cGAMP production. Results These results unravel a novel nuclear cooperative role of cGAS and IFI16 and extend the cGAS DNA sensing and its enzymatic activity in the nucleus. IFI16 acetylation required for inflammasome complex formation is cGAS independent. The cGAS-pro-Caspase1 and cGAS-ASC interaction suggests plausible role of cGAS in inflammasome complex for Caspase-1 activation. The activated Caspase-1 interaction with cGAS was also observed. Further, the autophagy and DNA damage responses elicited during de novo HSV-2 infection are suggested. Discussion The crosstalk of the type I interferon pathway with the inflammasome, autophagy and DNA damage response pathways suggests an intricate mechanism of inter-regulation at different stages and time points during infection, that might orchestrate a balanced and efficient immune response or facilitate viral immune evasion. Unique and dynamic post translational modifications of cGAS, namely acetylation and K-63 poly-ubiquitination, are observed, and are plausibly involved in cGAS regulation during HSV-2 infection.