Search Results (468)

Background/Objectives: Lipid nanoparticles (LNPs) have emerged as crucial vehicles for messenger RNA (mRNA) applications in antitumor therapy. Combining LNPs with stimulator of interferon genes (STING) activation holds promise for treating “cold” tumors such as pancreatic cancer. However, two major challenges remain: inefficient mRNA escape from endosomes and STING pathway suppression in immunosuppressive tumor microenvironments. Methods: To improve endosomal escape, we developed a novel pH-responsive PEGylated lipid (Ben-mPEG₂₀₀₀) for mRNA-LNP preparation while using commercial Man-mPEG₂₀₀₀ for dendritic cell (DC)-targeted delivery of LNPs; to alleviate suppression of the STING pathway in the tumor microenvironment and activate immune responses, STING-R283S mRNA was encapsulated into LNPs, ultimately resulting in DC-targeted/pH-responsive LNPs loaded with STING-R283S mRNA for pancreatic cancer immunotherapy research. Results: After pH-responsive cleavage, Ben-mPEG₂₀₀₀ not only enhanced the positive charge of LNPs through the exposed protonated amino groups but also eliminated the PEG-induced steric hindrance effect. The combination of these two effects promoted membrane fusion between LNPs and the endosome, thereby enhancing mRNA translation. As a payload, STING-R283S could further amplify STING signaling in DCs without cytotoxicity to counteract immunosuppression in pancreatic cancer. Conclusions: This engineered LNP platform enhanced mRNA expression and STING activation in DCs, improving immunotherapy outcomes in pancreatic cancer. Full article

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, and residual inflammatory risk persists despite optimal lipid and glucose control. Emerging evidence indicates that metabolic reprogramming within immune cells constitutes a central driver of cardiovascular immune injury. In this review, we propose a unifying framework in which glyco-lipotoxicity acts as a primary metabolic trigger, inducing mitochondrial dysfunction, oxidative stress, and activation of the NLRP3 inflammasome and cGAS–STING pathways. Hyperglycaemia and dyslipidaemia reshape intracellular metabolic circuits, enhancing glycolysis and disrupting oxidative phosphorylation, thereby promoting sustained pro-inflammatory phenotypes. Crucially, metabolic intermediates function as cofactors for epigenetic remodelling. This establishes trained immunity in both circulating innate immune cells and haematopoietic stem/progenitor cells, which serves as the cellular basis for persistent metabolic memory. This persistent immunometabolic imprint amplifies sterile inflammation and accelerates vascular and myocardial remodelling. Furthermore, these processes are systemically propagated through cross-organ communication networks, including the heart–adipose, gut–heart, and cardio-hematopoietic axes, forming a multidimensional inflammatory amplification loop. We also summarise emerging therapeutic strategies targeting the metabolic–epigenetic axis, aiming to reverse maladaptive trained immunity and mitigate residual CVD risk. By integrating immunometabolism, epigenetic regulation, and organ crosstalk, this review highlights metabolic reprogramming as a pivotal mechanistic nexus and potential precision target for cardiovascular protection. Full article

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article

Highly pathogenic avian influenza (HPAI) is a lethal disease of poultry that has recently spilled over into mammals, including dairy cattle and humans, heightening concerns for livestock health, food security, and pandemic emergence. While vaccines that induce neutralizing antibodies against hemagglutinin and neuraminidase provide strain-specific protection, durable cross-subtype immunity requires T-cell responses targeting conserved internal antigens such as nucleoprotein (NP). To leverage these conserved targets, we utilized a previously engineered mosaic nucleoprotein (MNP) incorporating T-cell epitopes from thousands of influenza A virus (IAV) strains, conferring broad protection against epidemic (H3N2) and pandemic (H1N1) IAV in mice. Here, we tested whether precision adjuvancy could differentially imprint adaptive immunity to MNP in cattle. Combination formulations paired the carbomer-based nano-emulsion Adjuplex (ADJ) with either a STING agonist (cyclic dinucleotides; CdN) or a TLR4 agonist (glucopyranosyl lipid A; GLA) to program distinct inflammatory milieus. Both formulations elicited circulating IFN-γ–producing T cell responses and NP-specific antibodies in serum and milk. However, STING activation via CdN generated more potent and consistent cellular and humoral immunity than TLR4 engagement. These data demonstrate that selective activation of innate sensing pathways functionally imprints adaptive immune magnitude and quality in a large animal host. By advancing a broadly protective, T-cell-focused vaccine strategy in cattle, this work supports a One Health framework to mitigate H5N1 transmission risk at the human–animal interface. Full article

The gut microbiota of fish plays a crucial role in nutrition, metabolism and immune regulation, and is highly sensitive to environmental stressors such as pesticide exposure. This study investigated the effects of emamectin benzoate (EMB) exposure on Asian stinging catfish (Heteropneustes fossilis) gut microbiota using an integrated culture-dependent and culture-independent approach to assess functional and taxonomic dysbiosis. Gut smear samples from control and EMB-treated fish at two sublethal concentrations (0.5 µg/L and 5 µg/L) were analyzed for major functional bacterial groups, including heterotrophic, lipid-hydrolysing, starch-hydrolysing, spore-forming, and Gram-negative bacteria and Pseudomonas spp., using standard plate count techniques. In parallel, microbial community composition and diversity were examined through 16S rRNA (V3–V4 region) gene amplicon sequencing followed by bioinformatic analysis. Culture-based results showed a significant decline in total heterotrophic bacteria and key functional groups in EMB-treated fish, indicating suppression of microbial metabolic activity and functional imbalance. Lipid-hydrolysing and starch-hydrolysing bacteria showed pronounced sensitivity to pesticide exposure, while spore-forming bacteria exhibited a marked reduction, suggesting compromised microbial resilience. Although Gram-negative bacteria declined overall, Pseudomonas spp. displayed a non-linear response, with an initial decrease, followed by partial recovery under higher exposure. Culture-independent analysis demonstrated reduced alpha diversity, altered community structure, and taxonomic shifts in EMB-treated fish. Pseudomonadota exhibited a distinct pattern characterized by decline at 0.5 µg/L and partial recovery at 5 µg/L, reflecting adaptive tolerance rather than restoration of microbial homeostasis. Overall, the combined evidence indicates pronounced EMB-induced gut dysbiosis at both functional and compositional levels. This study highlights the fish gut microbiome as a sensitive biomarker of stress and underscores the ecological risks associated with EMB in aquatic environments. Full article

Carfilzomib (CFZ) is a proteasome inhibitor primarily used to treat relapsed and refractory multiple myeloma. However, its clinical application is limited by significant cardiotoxicity, the underlying mechanisms of which remain incompletely understood. In this study, we aimed to elucidate the pathogenic pathways involved. In vitro, CFZ induced mitochondrial dysfunction and apoptosis in AC16 cardiomyocytes in a concentration- and time-dependent manner. Transcriptomic analysis revealed enrichment in pathways related to autophagy and endoplasmic reticulum stress. Mechanistically, CFZ promoted autophagosome formation but downregulated the SNARE proteins STX17, SNAP29, and VAMP8, thereby impairing autophagosome–lysosome fusion and blocking autophagic flux. This disruption was associated with the activation of the cGAS-STING signaling pathway. In vivo, CFZ administration resulted in cardiac dysfunction and apoptosis in mice, both of which were attenuated by the STING inhibitor C-176. Consistently, STING knockdown restored autophagic flux and reduced cardiomyocyte injury in vitro. In conclusion, CFZ induces cardiotoxicity by activating the cGAS-STING pathway, which disrupts the autophagic clearance of damaged mitochondria and promotes cardiomyocyte apoptosis. Targeting STING may represent a promising therapeutic strategy to mitigate CFZ-induced cardiotoxicity. Full article

Background/Objectives: Dermatomyositis is an autoimmune disease with heterogeneous symptoms and many potential drivers. Nonpsychoactive cannabinoids have shown promise in treating some subtypes of DM; however, the reasons behind this were unclear. In this project, we tested the effects of CB2R activation on PBMCs from amyopathic and classic DM patients to determine its anti-inflammatory effects on pathways biologically relevant to DM. Methods: We determined the % CB2R positivity and intracellular cytokines in PBMCs from amyopathic DM and classic DM patients. CB2R positivity was determined by analyzing patient PBMCs via flow cytometry. PBMCs were stimulated by dsRNA for RIG1, dsDNA for cGAS, LPS for TLR4, and LPS/ATP for NLRP3, with and without CB2R pretreatment, and IFNβ, IFNγ, p65 NFkB, and pSTING levels were used as markers of pathway activation. The CB2R agonist JWH133 was used to pretreat PBMCs before stimulation. Results: Amyopathic DM PBMCS were found to be 101.3% more positive for CB2R compared to classic DM PBMCS (p < 0.05). In amyopathic DM PBMCs stimulated by LPS/ATP to target the NLRP3 inflammasome, CB2R activation resulted in a significant reduction in IFNβ MFI for MoDCs (p < 0.05) and Macs (p < 0.05), with a similar trend observed in cDCs relative to classic DM PBMCS. On the other hand, no difference in IFNβ response to CB2R activation was observed across all cell types investigated between classic and amyopathic DM PBMCs stimulated with LPS only to target TLR4. Conclusions: Amyopathic DM PBMCs were significantly more positive for CB2R and had better anti-inflammatory responses to CB2R activation for many inflammatory pathways implicated in DM. Full article

Background/Objectives: The integration of locoregional and systemic therapies represents a promising strategy in hepatocellular carcinoma (HCC). Yttrium-90 (Y-90) radioembolization provides durable local tumor control, while immune checkpoint inhibitors (ICIs) improve systemic disease outcomes. This review evaluates the biological rationale, clinical evidence, and emerging role of combination Y-90 radioembolization and immunotherapy in HCC. Methods: A semi-systematic (PRISMA-informed) literature review of PubMed/MEDLINE through September 2025 was conducted, including clinical trials, retrospective and prospective studies, and translational investigations evaluating Y-90 radioembolization, immunotherapy, and their combination. Results: Preclinical and translational studies demonstrate that Y-90 radioembolization induces immunogenic cell death, enhances antigen presentation, and activates immune pathways including interferon signaling and STING-mediated responses, supporting a mechanistic basis for potential synergy with ICIs. Early clinical studies, including phase I/II trials, report objective response rates ranging from approximately 30% to 41.5% and median overall survival up to 20.9 months in selected populations. Treatment-related grade ≥ 3 adverse events range from 10% to 25%, comparable to monotherapy approaches. However, outcomes vary across heterogeneous patient populations, and cross-trial comparisons remain limited. Ongoing prospective trials are evaluating combination strategies incorporating contemporary first-line regimens, including atezolizumab plus bevacizumab and the STRIDE regimen. Conclusions: Combination Y-90 radioembolization and immunotherapy demonstrates a strong biological rationale and encouraging early clinical signals, with acceptable safety profiles. However, current evidence remains preliminary and derived from non-randomized studies. Ongoing randomized trials are required to define optimal patient selection, treatment timing, and sequencing, and to establish whether combination therapy provides meaningful benefit over current standards of care. Full article

Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS–STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts. Full article

Background/Objectives: This study aimed to develop a novel tumor-associated macrophage (TAM)-targeting nanoplatform to improve the solubility and bioavailability of camptothecin (CPT) and achieve active targeted drug delivery for enhanced anti-tumor immunotherapy. Methods: We constructed a sialic acid-disulfide bond-camptothecin (SA-SS-CPT) nanowire system. Sialic acid was used as a targeting ligand to specifically recognize the overexpressed Siglec-E receptor on TAMs. Upon cellular internalization, the disulfide bond was designed to respond to intracellular glutathione (GSH), enabling controlled drug release. Results: The SA-SS-CPT nanowires significantly improved CPT solubility and enabled targeted delivery to TAMs. Following GSH-responsive cleavage and CPT release, the nanowires induced DNA damage in TAMs, activating the cGAS-STING signaling pathway. This promoted TAM polarization toward the M1 phenotype, enhanced pro-inflammatory and anti-tumor immune responses, and inhibited tumor immune escape. Furthermore, SA-SS-CPT synergistically improved the efficacy of PD-L1 blockade immunotherapy, remodeling the tumor immune microenvironment. Conclusions: The SA-SS-CPT nanoplatform effectively targets TAMs, repolarizes them to an anti-tumor M1 phenotype, and activates the cGAS-STING pathway. It shows strong potential for overcoming tumor immune escape and synergizing with PD-L1 checkpoint blockade to achieve significant tumor clearance. Full article

Butyrophilin-like 2 (BTNL2) is an immunomodulatory molecule critically involved in regulating the host immune response to infection with the avirulent Mycobacterium tuberculosis strain H37Ra. However, its functional role in modulating pyroptosis and associated inflammatory responses remains incompletely characterized. Here, we demonstrate that BTNL2 deficiency exacerbates pyroptosis and the inflammatory response in H37Ra-infected murine peritoneal macrophages via two distinct pathways. First, the loss of BTNL2 induces excessive mitochondrial damage, which leads to aberrant release of mitochondrial DNA (mtDNA) and accumulation of mitochondrial reactive oxygen species (mtROS), thereby triggering NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis. Second, cytosolic mtDNA accumulation hyperactivates the cGAS–STING signaling axis, resulting in transcriptional upregulation of NLRP3 and consequent amplification of pro-inflammatory cytokine production. Collectively, these findings demonstrate that BTNL2 acts as a regulator of mitochondrial homeostasis and innate immune balance during H37Ra infection in primary peritoneal macrophages. The results provide mechanistic insights into BTNL2 function in the context of H37Ra-induced pyroptosis. Full article

Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013–2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans. Full article

Transposable elements (TEs) are increasingly recognized as modulators of innate immunity, yet their antiviral functions remain poorly understood outside mammals and dipterans. Here, we identify a long terminal repeat retrotransposon, LmGypsy, as a key regulator of antiviral defense in Locusta migratoria. The infection of Acrididae reovirus (ARV) induces rapid upregulation of LmGypsy, and its inhibition compromises antiviral resistance. Mechanistically, LmGypsy promotes viral-derived DNA (vDNA) production, which drives Dicer-2-dependent biogenesis of virus-derived small interfering RNAs (vsiRNAs) to enhance RNA interference-mediated viral clearance. Notably, vDNA persists throughout infection, suggesting a role in sustaining antiviral responses. In parallel, LmGypsy activity is positively associated with induction of cyclic GMP-AMP synthase (cGAS)-like receptors (LmcGAS1/2/4) and their downstream effector Stimulator of Interferon Genes (STING). Together, these findings support a dual-layer antiviral strategy and indicate that TE-mediated immunity represents a widespread antiviral mechanism across taxa. Full article

Infertility and ovarian ageing are increasingly acknowledged as illnesses affected not just by endocrine decline but also by chronic inflammatory stress and mitochondrial dysfunction in the reproductive milieu. The cGAS-STING signalling pathway has emerged as a significant possibility linking these activities. The cGAS-STING pathway, originally defined as a cytosolic DNA-sensing mechanism essential for innate immune defence, is now recognised as a broader modulator of sterile inflammation, cellular senescence, and tissue failure. Experimental reproductive models suggest that the activation of this system may operate as a crucial link between mitochondrial dysfunction, cytosolic DNA accumulation, inflammatory cytokine production, and the progressive decline of ovarian and endometrial function. The activation of cGAS-STING in granulosa cells has been associated with inflammatory signalling and impaired steroidogenic activity. Full article

Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a “double-edged sword” that greatly influences the success of immune checkpoint inhibitors (ICIs). On the one hand, RT acts like an in situ vaccine, causing immunogenic cell death and activating the cGAS-STING pathway, which leads to dendritic cell maturation, T-cell infiltration, and reactive PD-L1 expression. This effect can turn “cold” tumors into “hot” ones, making them more responsive to immune checkpoint blockade. On the other hand, RT can lead to resistance to ICIs by promoting an immunosuppressive environment, recruiting regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. This review analyzes the mechanisms behind this immunological duality and assesses how parameters such as dose, fractionation, and particle type (e.g., carbon ion versus photon therapy) can be optimized to enhance immune activation. Lastly, we discuss future strategies that focus on innate immunity and tumor metabolism, showing how targeting nutrient depletion and ferroptosis can break down immunosuppressive barriers and position RT as an essential component of precision immuno-oncology. Full article