Search Results (290)

Mitochondrial stress has emerged as a key regulator of tumor–immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor–immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade. Full article

Periodontitis is a chronic inflammatory disease remaining elusive with its pathogenesis. Mitochondrial dysfunction and aberrant immune activation are implicated, but the underlying mechanisms remain incompletely understood. Given the essential role of Ca²⁺ homeostasis in maintaining normal mitochondrial function, we investigated the role of mitochondrial calcium (mtCa²⁺) dysregulation in periodontitis. Gingival tissues from periodontitis patients and healthy controls, as well as cultured gingival fibroblasts stimulated with Porphyromonas gingivalis lipopolysaccharide, were examined using transmission electron microscopy, confocal imaging, flow cytometry, qPCR, and western blotting. Notably, mtCa²⁺ was overloaded under inflammatory conditions, accompanied by disruption of whole-cell Ca²⁺ homeostasis. We also observed marked mitochondrial ultrastructural damage, mitochondrial DNA (mtDNA) leakage, and activation of the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway. The mitochondrial Ca²⁺ channel proteins, voltage dependent anion channel 1 (VDAC1) and mitochondrial calcium uniporter (MCU), were significantly upregulated in periodontitis gingiva, and their expression positively correlated with probing depth. Pharmacological inhibition of VDAC1 or MCU attenuated mtCa²⁺ overload, reduced mtDNA release and downregulated pro-inflammatory cytokines. These findings link mtCa²⁺ overload to mtDNA leakage and innate immune activation in periodontitis, and identify VDAC1 and MCU as promising therapeutic targets to restore mtCa²⁺ homeostasis and control host immune responses. Full article

Background: Renal aging represents a pivotal contributor to the pathogenesis and progression of age-related kidney disorders. D-Pinitol (DP), a bioactive cyclitol naturally present in food plants, exhibits multiple beneficial biological activities. Nevertheless, its role in counteracting renal aging remains unclear. Methods: This study employed both in vitro (HK-2 cells) and in vivo (C57BL/6J mice) models of D-galactose (DG)-induced renal aging. A panel of experimental approaches was applied to characterize the protective effects and molecular mechanisms of DP against renal aging, including Western blot, qPCR, ELISA, transcriptomic profiling, transmission electron microscopy, surface plasmon resonance (SPR), immunohistochemistry, and immunofluorescence staining. Results: DP significantly attenuated DG-induced renal aging-like changes in vitro and in vivo by preserving mitochondrial function and alleviating inflammatory responses. Transcriptomic analysis suggested SARM1 as a potential key target responsible for the beneficial effects of DP. In DG-induced aging models, SARM1 was remarkably upregulated in a tubule-specific pattern and acted as a critical mediator of mitochondrial dysfunction. Damaged mitochondria released mtDNA, which further activated the cGAS–STING innate immune signaling pathway, consequently promoting the senescence-associated secretory phenotype (SASP) and renal inflammation. Mechanistically, molecular docking and related assays suggested that DP may stabilize the auto-inhibitory conformation of SARM1, thereby potentially preventing its activation. Conclusions: DP attenuates DG-induced renal aging-like changes via suppressing the SARM1–cGAS–STING axis, thereby restoring mitochondrial homeostasis and mitigating inflammation. Given the lack of effective interventions targeting renal aging, these findings suggest SARM1 as a novel potential therapeutic target for renal aging and highlight DP as a promising food-derived anti-aging ingredient for renal protection. Full article

The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO₂)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H₂O₂) and glutathione (GSH) to generate oxygen (O₂), reactive oxygen species (ROS), and manganese (Mn²⁺). A dual strategy of “oxygen supplementation” and “small-molecule inhibition” synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn²⁺ and damaged DNA synergistically activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation. Full article

The innate immune signaling pathway cGAS–STING plays an important role in the recognition of cytosolic nucleic acids and the induction of the interferon-dependent antiviral response. Despite the significant research interest in this cascade in the context of immune system function, the mechanisms regulating cGAS–STING signaling and the switch between its pro-inflammatory and pro-apoptotic effects remain largely underexplored. According to publicly available RNA-seq data and microarray analyses, SETD7 lysine methyltransferase participates in interferon signaling in cancer cells. This study aims to elucidate the role of SETD7 in the regulation of the STING-dependent immune response in human lung adenocarcinoma (LUAD) cells. For this purpose, we developed a reproducible and cost-effective method for inducing the STING cascade by transfecting cells with salmon sperm DNA (sspDNA). We demonstrated that sspDNA efficiently induces phosphorylation of the key components of the STING–TBK1–IRF3 signaling pathway and activates the expression of interferons and pro-inflammatory cytokines. Using this approach, we further demonstrated that SETD7 is involved in the regulation of the IRF3-dependent transcriptional program. Suppression of SETD7 was associated with changes in the expression of genes related to innate immune response and apoptosis, including increased levels of IFNA1, IL1B, BAK1, BBC3 (PUMA), and BCL2. Furthermore, attenuation of SETD7 expression reduced the lentiviral transduction efficacy in H1299 cells. These results suggest that SETD7 may play a role in regulating the switch in STING signaling between pro-inflammatory and pro-apoptotic responses in LUAD cells. Full article

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies. Full article

Mitochondria are essential organelles that perform irreplaceable functions in neurons. The degeneration of neurons in Alzheimer’s disease (AD) is associated with mitochondrial damage, and Tau pathology represents a significant pathogenic factor in AD. However, the relationship between Tau and mitochondrial dysfunction during neuronal degeneration remains unclear. In this study, we investigated the effects and mechanisms by which extracellular Tau aggregates induce neuronal mitochondrial damage and dysfunction. The results showed that extracellular Tau aggregates lead to structural damage of mitochondria in SH-SY5Y cells and disrupt mitochondrial homeostasis. Extracellular Tau aggregates can also cause mitochondrial oxidative stress and inhibit oxidative phosphorylation in SH-SY5Y cells. Concurrently, extracellular Tau aggregates promote neuronal death through an increase in cytochrome C, mtDNA leakage and activation of the cGAS/STING pathway. We also explored the effects of a single-chain variable fragment antibody (scFv T1) and found that scFv T1 alleviated mitochondrial damage and dysfunction by inhibiting the formation of Tau aggregates. These findings suggest that targeting Tau pathology may be crucial to address neuronal mitochondrial impairment and that reduction of the toxicity associated with extracellular Tau aggregates could help slow Tau pathology progression. Full article

Metal ion-based chemo-immunotherapy is often limited by rigid intracellular metal homeostasis, insufficient reactive oxygen species (ROS) accumulation, and an immunosuppressive tumor microenvironment (TME). To overcome these limitations, we engineered an ATP-responsive, core–shell bimetallic nanoreactor (Cu/ZIF@PDA, termed CZP) featuring a precisely controlled ~25 nm biomimetic polydopamine (PDA) coating. Triggered by elevated tumoral ATP levels, CZP undergoes coordination-induced disassembly and promotes oxidative stress amplification. Specifically, the PDA shell acts as a superoxide dismutase (SOD) mimetic to continuously supply H₂O₂, fueling Cu²⁺-mediated Fenton-like reactions to unleash highly toxic hydroxyl radicals (•OH) while aggressively depleting the intracellular glutathione (GSH) pool. This irreversible oxidative damage, coupled with Zn²⁺-induced mitochondrial dysfunction, triggers profound mitochondrial DNA (mtDNA) leakage. Crucially, this cytosolic DNA robustly activates the cGAS-STING signaling axis, driving a massive surge in immunogenic cell death (ICD) and significantly promoting dendritic cell (DC) maturation. Furthermore, CZP markedly inhibited primary tumor growth in vivo and showed protection in a tumor re-challenge model, accompanied by enhanced dendritic cell maturation. These findings support the potential of this ATP-responsive bimetallic nanoplatform to promote antitumor immune activation. Full article

Manganese ions (Mn²⁺) are an essential trace element within organisms spanning the entire tree of life. It has reported that Mn²⁺ exerts strong immunocompetence effects and exhibits antiviral effects against various human and animal viruses, including DNA and RNA viruses. Recently, Mn²⁺ has been found to be involved in the activation of the innate immune DNA-sensing cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway and subsequent antiviral function. However, the antiviral mechanism of Mn²⁺ remains unclear. In the current study, the results suggest that the cGAS-STING pathway is essential for Mn²⁺ to promote interferon (IFN) signaling, but it is not essential for triggering antiviral functions. After knocking out the STING or interferon regulatory factor 3 (IRF3) gene, Mn²⁺ still retains its antiviral activity against herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). Furthermore, the results from transcriptomic analysis indicate that Mn²⁺ can induce a significant change in the apoptotic process in STING⁻/⁻ 3D4/21 cells. Mn²⁺ can induce cell apoptosis through the oxidative stress pathway, and inhibiting the apoptotic signal could suppress Mn²⁺-mediated antiviral activity in STING⁻/⁻ 3D4/21 cells. Additionally, dual knockout of IRF3 and caspase3, resulting in concurrent loss of IFN and apoptotic signals, eliminates the antiviral effects of Mn²⁺. In summary, the current study suggests that Mn²⁺ could exert antiviral effects not only through the cGAS-STING-IFN pathway but also via the reactive oxygen species (ROS)-apoptosis pathway. Full article

Background: Prostate cancer (PCa) arises from complex interactions among host genetics, androgen signaling, and microbial communities. Emerging genomic evidence supports the presence of microbial consortia within prostate tissue, suggesting that microbial genes, metabolites, and host–microbe interactions may contribute to chronic inflammation, oncogenic signaling, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published between 2020 and 2025, complemented by selected mechanistic reports published in March 2026. Human studies and experimental research providing mechanistic insights into prostate models were prioritized. Due to the heterogeneous methodologies, evidence was synthesized qualitatively, with an emphasis on genomic and signaling perspectives. Results: Low-biomass microbial DNA is consistently detected in prostate tissue. Proteomic analyses of Corpora amylacea suggest a “fossil record” of past infections through sequestered microbial DNA and antimicrobial proteins, potentially priming tissue for long-term carcinogenic processes, although contamination remains a key limitation. Recurrent bacterial and viral signals, including Cutibacterium acnes, Escherichia coli, Pseudomonas, Acinetobacter, human papillomavirus, Epstein–Barr virus, and cytomegalovirus, appear to converge on a restricted set of tumor-relevant pathways, including TLR–NF-κB, MAPK, PI3K/AKT/mTOR, cGAS–STING, and p53/pRb disruption. These interactions may promote cytokine production, oxidative stress, DNA damage, epithelial–mesenchymal transition, extracellular matrix remodeling, immune evasion, and resistance to therapy. The gut–prostate axis further links intestinal dysbiosis and microbial metabolites with systemic IGF-1 signaling and castration resistance. Conclusions: Microbial genomic consortia in the prostate and gut may shape inflammatory, metabolic, and immune networks that influence PCa initiation and progression. However, most available data remain correlative and are limited by low-biomass sampling, contamination risk, and heterogeneous study designs. Future research should prioritize rigorous contamination control, longitudinal and prostate-specific mechanistic studies, and integrated multi-omic approaches to clarify causality and identify actionable microbial targets for prevention, diagnosis, and therapy. Full article

Glioblastoma (GBM) remains among the most treatment-refractory human malignancies. It is characterized by profound radioresistance and a highly immunosuppressive tumor microenvironment, limiting the durable efficacy of radiotherapy. Beyond direct cytotoxicity, ionizing radiation can induce immunogenic cell death and the release of damage-associated molecular patterns (DAMPs), including surface-exposed calreticulin, HMGB1, extracellular ATP/adenosine, and tumor-derived DNA. These signals engage pattern-recognition receptors and cGAS–STING–type I interferon pathways, transiently promoting antigen presentation and immune activation. In GBM, however, DAMP signaling frequently evolves toward chronic inflammation and immune suppression, characterized by myeloid cell recruitment, adenosine accumulation, and immune checkpoint upregulation, thereby contributing to tumor regrowth and radioresistance. This dual immune-regulatory role of DAMPs highlights the importance of temporal and contextual interpretation of radiation-induced immune responses. In this review, we summarize current mechanistic and translational evidence on DAMP-mediated immunomodulation in GBM radiotherapy; discuss modality-dependent considerations across photon, proton, and high-LET irradiation; and evaluate the emerging potential of DAMPs as dynamic biomarkers of treatment response. We further outline how integration of DAMP profiling with liquid biopsy, imaging, and nanotheranostic platforms may support biologically informed and adaptive radiotherapy strategies for glioblastoma. Full article

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway serves as a central innate immune signaling axis in host defense against DNA virus infections, and RNA viruses have also evolved diverse strategies to counteract this pathway. Encephalomyocarditis virus (EMCV), a zoonotic RNA virus, utilizes its 2C protein to antagonize RIG-I-like receptor-mediated type I interferon signaling and induce autophagic degradation of calcium binding and coiled-coil domain 2, thereby evading host antiviral immunity. However, the precise molecular mechanism by which EMCV 2C protein modulates the cGAS-STING pathway remains incompletely understood. Herein, we show that EMCV infection reduces the expression of cGAS and STING proteins, and its 2C protein significantly suppresses the production of IFN-β triggered by poly(dA:dT) or viral infection, as well as the mRNA expression of interferon-stimulated genes. Mechanistically, 2C protein binds to STING via its ATPase domain and facilitates K48-linked polyubiquitination and proteasomal degradation of STING, while dominantly interfering STING translocation to the Golgi apparatus and the formation of STING-TBK1-IRF3 complex, thereby blocking STING-mediated IFN-β signal transduction at multiple levels. This study reveals a novel mechanism by which the EMCV 2C protein suppresses the host antiviral response by targeting STING and promoting its ubiquitination and degradation. This finding deepens understanding of the immune evasion mechanism of EMCV and provides a theoretical foundation for the development of antiviral therapies targeting the 2C protein of picornaviruses. Full article

Autophagy is a fundamental lysosome-dependent degradation process that maintains cellular homeostasis in response to stress. VSP34 (Vacuolar Protein Sorting 34, PIK3C3) is the only class-III phosphatidylinositol 3-kinase and generates phosphatidylinositol 3-phosphate (PI3P) for auto-phagosome nucleation and maturation. Thus, it provides a critical adaptive survival pathway for cells that are experiencing metabolic stress. The VPS34–autophagy axis plays dual roles in cancer, which depend on the context: it can restrain early tumorigenesis, but in established tumors, it can promote survival in conditions of hypoxia, nutrient deprivation, and therapeutic pressure. Moreover, VPS34 shapes the tumor microenvironment (TME) through its influence on both immune and cancer cells by modulating autophagy, cGAS-STING (cyclic GMP-AMP synthase Stimulator of Interferon Genes), and STAT1 pathways. VPS34 inhibition has been reported to induce an interferon response that increases CD8⁺ T and natural killer (NK) cell infiltration and converts cold tumors into hot ones. This behavior suggests that combining VPS34 inhibitors with cancer immunotherapies could be beneficial. In this review, we summarize the molecular functions and regulations of VPS34 in autophagy and discuss recent advances linking VPS34 to tumor and cancer immunotherapy. Full article

Cells rely heavily on DNA repair networks to survive genomic damage. For repairing double-strand breaks, Non-Homologous End Joining (NHEJ) remains the primary pathway, which is largely controlled by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Researchers have long studied how phosphorylation drives this kinase. However, recent data point to an important additional layer of control. Drawing on evidence accumulated over the past two decades, we propose a “Spatiotemporal Logic Circuit” model for DNA-PKcs regulation. In this model, SUMO-associated interactions may help stabilize synaptic assembly, HUWE1-mediated neddylation may facilitate kinase activation at Lys4007, and K48-linked ubiquitination—potentially involving RNF144A—may contribute to the turnover of persistent repair complexes. Importantly, we frame these UBL-mediated events within the broader autophosphorylation-driven conformational cycle of DNA-PKcs, which remains central to NHEJ progression. Additionally, we highlight the structural interface where activation and degradation signals may converge and the extraction barrier posed by the massive DNA-PKcs scaffold. From a translational perspective, we argue that the exceptional size of DNA-PKcs (~470 kDa) and its topological entrapment on DNA render it an unusually challenging PROTAC target—one that may require p97/VCP-assisted extraction before proteolysis can proceed. We also highlight the underappreciated risk that E3 ligase loss-of-function, already documented in BET-PROTAC resistance, may similarly undermine DNA-PKcs degrader strategies. Full article

Ginkgetin (GK) is a naturally occurring biflavonoid predominantly isolated from Ginkgo biloba and has attracted increasing attention because of its broad pharmacological activities. Structurally, GK belongs to the 3′-8″-linked biflavone subclass, which distinguishes it from other biflavonoids like amentoflavone (the parent compound of this subclass) and its monomeric counterparts such as apigenin. This unique C-C linked dimeric architecture confers distinct molecular planarity and lipophilicity, contributing to its enhanced membrane permeability and multitarget engagement capabilities. GK has been shown to exert pleiotropic biological effects in preclinical studies, including anti-inflammatory, antioxidant, antifibrotic, anticancer, neuroprotective, cardioprotective, metabolic regulatory and antibacterial activities. Mechanistically, preclinical evidence indicates that GK functions as a multitarget modulator of key signaling pathways involved in oxidative stress, inflammation, cell death and tissue remodeling, such as nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), nuclear factor kappa-B(NF-κB), Janus kinase/signal transducer and activator of transcription(JAK/STAT), mitogen-activated protein kinases(MAPKs), AMP-activated protein kinase/mechanistic target of rapamycin(AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) and cyclic GMP-AMP synthase–stimulator of interferon genes(cGAS–STING). Notably, GK has been observed to display context-dependent regulation of cell fate decisions, including apoptosis, autophagy and ferroptosis, thereby enabling the selective elimination of pathological cells while preserving normal tissue function. Preclinical studies further demonstrate that GK exhibits therapeutic potential across diverse disease systems, including cancer, metabolic disorders, cardiovascular diseases, neurological disorders and musculoskeletal diseases. In addition, emerging evidence highlights its antibacterial and antivirulence properties through the inhibition of biofilm formation and quorum sensing. It is crucial to note, however, that this promising profile is predominantly derived from preclinical studies, and clinical evidence in humans remains to be established. Despite these promising findings, the clinical translation of GK remains limited by challenges related to pharmacokinetics, bioavailability and druggability. This review systematically summarizes the chemical characteristics, pharmacological activities and molecular mechanisms of GK, with an emphasis on its multitarget actions and therapeutic potential across disease systems, and discusses current limitations and future perspectives to facilitate the rational development of GK-based interventions. Full article