Search Results (2,124)

Nontuberculous mycobacteria are opportunistic pathogens increasingly associated with human disease. Within this group, the Mycobacterium avium complex (MAC), which includes M. avium, M. intracellulare and M. intracellulare subsp. chimaera, is the most frequent cause of infection. The increase in MAC cases worldwide has made it crucial to understand their population structure, clinical relevance and resistance mechanisms. Recent advances in whole-genome sequencing (WGS) and molecular approaches have improved the knowledge of taxonomy, population structure and genetic diversity, while also enabling the investigation of transmission and epidemiology. Clinically, MAC most often causes chronic pulmonary disease, but extrapulmonary forms, including disseminated disease, also occur. Presentation can vary by infecting species, while host factors such as pre-existing lung disease or immunosuppression further increase the risk. Treatment outcomes remain less favourable than desired, in part due to antimicrobial resistance involving de novo-acquired mutations. Pathogenesis is also influenced by interactions between MAC and host cells, including mechanisms of immune evasion and inflammatory modulation. In addition, emerging evidence suggests that gut–lung axis dysbiosis may influence susceptibility to MAC infection. This review outlines current knowledge on the population structure, clinical significance, resistance and host–pathogen interactions of MAC. Full article

Immune checkpoint inhibitors (ICIs), including PD-L1 inhibitors, have been approved by the FDA for the treatment of cancers; however, only a small number of cancer patients benefit from these ICIs. Furthermore, the development of drug resistance to this type of treatment is often inevitable. The mechanisms of resistance to PD-L1 inhibitors can be attributed, in part, to an incomplete understanding of the regulation of PD-L1 protein expression. In this study, we identified the role of the E3 ligase GP78, also known as the Autocrine Motility Factor Receptor (AMFR), in the regulation of PD-L1 protein levels. We show that GP78 physically interacts with PD-L1, which is confirmed by IP and Western blotting and is supported by molecular modelling using AlphaFold2. Our modeling studies predict that the interface amino acids of the Ig1 domain of PD-L1 interact with the RING domain and a β-hairpin preceding the CUE domain of GP78. The crystal structure of the PD-1/PD-L1 complex reveals that the interaction with PD-1 is mediated by the Ig1 domain of PD-L1. Furthermore, proteasomal degradation of PD-L1 has been observed via GP78-mediated K48-linked ubiquitination, indicating a key regulatory role for GP78 in the downregulation of PD-L1. Because GP78 expression is inversely correlated with PD-L1 levels in cancer, these findings may have clinical implications for predicting tumor immune evasion and patient response to PD-1/PD-L1 blockade therapies. Taken together, these findings identify a previously unknown mechanism by which GP78 targets PD-L1 for ubiquitination and subsequent degradation in cancer cells, and suggest that blocking the interaction between PD-L1 and PD-1 by an E3 ligase is a novel strategy to improve immunotherapies for cancer patients. Full article

The breach of an interspecies barrier by RNA viruses has facilitated the emergence of lethal hCoVs, particularly SARS-CoV-2, resulting in significant socioeconomic setbacks and public health risks globally in recent years. Moreover, the high evolutionary plasticity of hCoVs has led to the continuous emergence of diverse variants, complicating clinical management and public health responses. Studying the evolutionary trajectory of hCoVs, which provides a molecular roadmap for understanding viruses’ adaptation, tissue tropism, spread, virulence, and immune evasion, is crucial for addressing the challenges of zoonotic spillover of viruses. Tracing the evolutionary trajectory of lethal hCoVs provides essential genomic insights required for risk stratification, variant/sub-variant classification, preparedness for outbreaks and pandemics, and the identification of critical viral elements for vaccine and therapeutic development. Therefore, this review examines the evolutionary landscape of the three known lethal hCoVs, presenting a focused narrative on SARS-CoV-2 variants under monitoring (VUMs) as of May 2025. Using advanced bioinformatics approaches and data visualization, the review highlights key spike protein substitutions, particularly within the receptor-binding domain (RBD), which drive transmissibility, immune escape, and potential resistance to therapeutics. The article highlights the importance of real-time genomic surveillance and intervention strategies in mitigating emerging variant/sub-variant risks within the ongoing COVID-19 landscape. Full article

Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases. Full article

Neutrophils are the most abundant immune cells in the human body. Neutrophil extracellular traps (NETs) have recently garnered significant attention as a novel, non-traditional mechanism for combating pathogenic microorganisms. Recent studies have shown that NETs play a crucial role in antiviral immunity, providing new perspectives on how neutrophils defend against viral invasion. Viruses not only induce NET formation through various mechanisms but have also developed multiple escape strategies targeting NETs. It is worth noting that NETs are a double-edged sword for the host: while they possess antiviral effects that inhibit viral spread and replication, their constituent components may also exacerbate tissue damage and play important pathological roles in the progression of certain viral infections. Therefore, a thorough understanding of the regulatory mechanisms and dynamic balance of NETs in viral infections is of critical importance. Additionally, since the components of NETs may vary depending on the stimulus, NET-related markers have the potential to serve as biomarkers for the severity and prognosis of viral diseases. This article provides a systematic review of the induction mechanisms, antiviral effects, viral escape strategies, and virus-induced NET-related immunopathological damage in viral infections, offering new insights for antiviral immunotherapy. Full article

Cytoskeleton-associated protein 4 (CKAP4) has emerged as a critical player in gastrointestinal (GI) cancer progression, diagnosis, and therapy. This comprehensive review synthesizes current knowledge on CKAP4′s multifaceted roles across GI malignancies, providing novel insights into its mechanisms of action and clinical potential. Its interaction with DKK1 and subsequent activation of the PI3K/AKT pathway underscores its role in promoting tumor growth. This review also highlights novel insights into CKAP4′s mechanisms of action beyond the well-established DKK1-CKAP4 axis, including its interaction with integrin β1 and involvement in angiogenesis through the FMNL2/EGFL6/CKAP4/ERK pathway. CKAP4′s impact on tumor microenvironment and immune evasion is elucidated, offering a new perspective on its contribution to cancer progression. In addition, CKAP4 arises as a promising serum biomarker for early detection and prognosis across multiple GI cancers, emphasizing its potential superiority over traditional markers. The therapeutic potential of targeting CKAP4 is extensively explored, including novel approaches like anti-CKAP4 antibodies and aptamers, and their synergistic effects with existing treatments. By integrating findings from esophageal, gastric, pancreatic, and colorectal cancers, this review provides a unique, comprehensive overview of CKAP4 in GI oncology, underscoring CKAP4′s potential to revolutionize GI cancer diagnosis and treatment and paving the way for future translational research. Full article

Metastases are responsible for the majority of cancer-related deaths and remain one of the most complex and therapeutically challenging hallmarks of cancer. The metastatic cascade involves a multistep process by which cancer cells invade local tissue, enter and survive in circulation, extravasate, and ultimately colonize distant organs. Increasingly, the tumor microenvironment (TME), particularly the extracellular matrix (ECM), has emerged as a central regulator of these steps. Far from being a passive scaffold, the ECM actively influences cancer progression through its biochemical signals, structural properties, and dynamic remodeling. Among ECM components, collagens play a particularly pivotal role by mediating tumor cell adhesion, migration, invasion, survival, immune evasion, and therapeutic resistance. This narrative review synthesizes current knowledge of the dual roles of collagen in the metastatic process, with a focus on the cellular and molecular mechanisms. We highlight how altered ECM architecture and signaling contribute to metastatic niche formation and explore the potential of targeting ECM components as a strategy to enhance cancer therapy and improve patient outcomes. Full article

Lung cancer remains the leading cause of cancer mortality, hindered by drug resistance, limited targeting, and low immunotherapy response. This review presents biomimetic superparamagnetic iron-oxide nanoparticles (SPIONs) as a next-generation theranostic platform. By cloaking SPIONs with cell membranes—macrophage, neutrophil, or cancer cell—we endow them with biological targeting, immune evasion, and deep lung penetration. Coupled with magnetic field-guided retention and real-time imaging, these systems enable precision hyperthermia, on-demand drug release, and immune microenvironment reprogramming. We critically compare membrane types, outline translational challenges, and propose a regulatory-aligned safety framework. This biomimetic strategy offers a dual diagnostic–therapeutic solution for lung cancer and potentially other solid tumors. Full article

Introduction: Fusobacterium nucleatum, a common oral microbe associated with periodontal disease, has emerged as a significant prognostic indicator in colorectal cancer (CRC). This organism is notably enriched in CRC tissues and is associated with reduced survival times and relapse. Fusobacterium is implicated in encouraging the development of chemoresistance through diverse tumor-promoting pathways that are increasingly being elucidated across molecular domains. Methods: This work uses a combined analysis of public data examining the role of F. nucleatum in CRC by investigating multiple transcriptomic datasets derived from co-culture infections in vitro. Results: In tandem with previously identified mechanisms known to be influenced by F. nucleatum, this analysis revealed that the bacterium activates multiple chemoresistance-associated pathways, including those driving inflammation, immune evasion, DNA damage, and metastasis. Notably, this study uncovered a novel induction of type I and type II interferon signaling, suggesting activation of a pseudo-antiviral state. Furthermore, pathway analysis (IPA) predicted altered regulation of several therapeutic agents, suggesting that F. nucleatum may compromise drug efficacy through transcriptional reprogramming. Conclusions: These findings reinforce the role of F. nucleatum in modulating host cellular pathways and support the hypothesis that bacterial association potentiates chemoresistance. Full article

SARS-CoV-2 variants have demonstrated distinct epidemiological patterns and clinical presentations throughout the COVID-19 pandemic. Understanding variant-specific differences at the respiratory epithelium is crucial for understanding their pathogenesis. Here, we utilized human nasal organoid air–liquid interface (HNO-ALI) cell cultures to compare the viral replication kinetics, innate immune response, and epithelial damage of six different strains of SARS-CoV-2 (B.1.2, WA, Alpha, Beta, Delta, and Omicron). All variants replicated efficiently in HNO-ALIs, but with distinct replication kinetic patterns. The Delta variant exhibited delayed replication kinetics, achieving a steady state at 6 days post-infection compared to 3 days for other variants. Cytokine analysis revealed robust pro-inflammatory and chemoattractant responses (IL-6, IL-8, IP-10, CXCL9, and CXCL11) in WA1, Alpha, Beta, and Omicron infections, while Delta significantly dampened the innate immune response, with no significant induction of IL-6, IP-10, CXCL9, or CXCL11. Immunofluorescence and H&E analysis showed that all variants caused significant ciliary damage, though WA1 and Delta demonstrated less destruction at early time points (3 days post-infection). Together, these data show that, in our HNO-ALI model, the Delta variant employs a distinct “stealth” strategy characterized by delayed replication kinetics and epithelial cell innate immune evasion when compared to other variants of SARS-CoV-2, potentially explaining a mechanism that the Delta variant can use for its enhanced transmissibility and virulence observed clinically. Our findings demonstrate that variant-specific differences at the respiratory epithelium could explain some of the distinct clinical presentations and highlight the utility of the HNO-ALI system for the rapid assessment of emerging variants. Full article

Iron oxide nanoparticles (IONPs) have emerged as key materials in magnetic hyperthermia (MH), a minimally invasive cancer therapy capable of selectively inducing apoptosis, ferroptosis, and other cell death pathways while sparing surrounding healthy tissue. This review synthesizes advances in the design, functionalization, and biomedical application of magnetic nanoparticles (MNPs) for MH, highlighting strategies to optimize heating efficiency, biocompatibility, and tumor targeting. Key developments include tailoring particle size, shape, and composition; doping with metallic ions; engineering multicore nanostructures; and employing diverse surface coatings to improve colloidal stability, immune evasion, and multifunctionality. We discuss preclinical and clinical evidence for MH, its integration with chemotherapy, radiotherapy, and immunotherapy, and emerging theranostic applications enabling simultaneous imaging and therapy. Special attention is given to the role of MNPs in immunogenic cell death induction and metastasis prevention, as well as novel concepts for circulating tumor cell capture. Despite promising results in vitro and in vivo, clinical translation remains limited by insufficient tumor accumulation after systemic delivery, safety concerns, and a lack of standardized treatment protocols. Future progress will require interdisciplinary innovations in nanomaterial engineering, active targeting technologies, and real-time treatment monitoring to fully integrate MH into multimodal cancer therapy and improve patient outcomes. Full article

Bone immunity represents a dynamic interface where skeletal homeostasis intersects with systemic immune regulation. We synthesize emerging paradigms by contrasting two functionally distinct microenvironments: the marrow cavity, a hematopoietic and immune cell reservoir, and cancellous bone, a metabolically active hub orchestrating osteoimmune interactions. The marrow cavity not only generates innate and adaptive immune cells but also preserves long-term immune memory through stromal-derived chemokines and survival factors, while cancellous bone regulates bone remodeling via macrophage-osteoclast crosstalk and cytokine gradients. Breakthroughs in lymphatic vasculature identification challenge traditional views, revealing cortical and lymphatic networks in cancellous bone that mediate immune surveillance and pathological processes such as cancer metastasis. Central to bone immunity is the neuro–immune–endocrine axis, where sympathetic and parasympathetic signaling bidirectionally modulate osteoclastogenesis and macrophage polarization. Gut microbiota-derived metabolites, including short-chain fatty acids and polyamines, reshape bone immunity through epigenetic and receptor-mediated pathways, bridging systemic metabolism with local immune responses. In disease contexts, dysregulated immune dynamics drive osteoporosis via RANKL/IL-17 hyperactivity and promote leukemic evasion through microenvironmental immunosuppression. We further propose the “brain–gut–bone axis” as a systemic regulatory framework, wherein vagus nerve-mediated gut signaling enhances osteogenic pathways, while leptin and adipokine circuits link marrow adiposity to inflammatory bone loss. These insights redefine bone as a multidimensional immunometabolic organ, integrating neural, endocrine, and microbial inputs to maintain homeostasis. By elucidating the mechanisms of immune-driven bone pathologies, this work highlights therapeutic opportunities through biomaterial-mediated immunomodulation and microbiota-targeted interventions, paving the way for next-generation treatments in osteoimmune disorders. Full article

Circular RNAs (circRNAs) are novel types of covalently closed single-stranded RNA formed by the backsplicing of precursor mRNAs (pre-mRNAs). Recently, circRNAs have been shown to play a crucial role in various diseases, including cancers, cardiovascular and cerebrovascular diseases, and autoimmune diseases. Accumulating evidence has demonstrated that both host-derived and virus-encoded circRNAs play pivotal roles during viral infection, including modulating viral entry, genome replication, latency establishment, and the host antiviral immune responses while simultaneously facilitating viral immune evasion. However, their roles during viral infections and circRNA-host interactions remain to be further investigated. Therefore, this article reviews the key characteristics and biological functions of circRNAs, as well as recent advances in understanding the interactions between circRNAs from different sources and viral infections, which will offer insights for developing therapies targeting virus-associated diseases. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and DNA damage, while inflammation driven by cytokine-regulated pathways accelerates tumourigenesis. We therefore conducted this narrative review to collate the available evidence on the link between iron homeostasis and inflammatory signalling in CRC and highlight potential diagnostic and therapeutic applications. Methods: This narrative review of preclinical and clinical studies explores the molecular and cellular pathways that connect iron regulation and inflammation to CRC. Key regulatory molecules, such as the transferrin receptor (TFRC), ferroportin (SLC40A1), ferritin (FTH/FTL), hepcidin, and IL-6, were reviewed. Additionally, we summarised the findings of transcriptomic, epigenomic, and proteomic studies. Relevant therapeutic approaches, including iron chelation, ferroptosis induction, and anti-inflammatory strategies, were also discussed. Results: Evidence suggests that CRC cells exhibit altered iron metabolism, marked by the upregulation of transferrin receptor (TFRC), downregulation of ferroportin, and dysregulated expression of ferritin. Inflammatory mediators such as IL-6 activate hepcidin and STAT3 signalling, which reinforce intracellular iron retention and oxidative stress. Increased immune evasion, epithelial proliferation, and genomic instability appear to be linked to the interaction between inflammation and iron metabolism. Other promising biomarkers include ferritin, hepcidin, and composite gene expression signatures; however, their clinical application remains limited. Although several preclinical studies support the use of targeted iron therapies and combination approaches with anti-inflammatory agents or immunotherapy, there is a lack of comprehensive clinical validation confirming their efficacy and safety in humans. Conclusion: Although preclinical studies suggest that iron metabolism and inflammatory signalling form an interconnected axis closely linked to CRC, translating this pathway into reliable clinical biomarkers and effective therapeutic strategies remains a significant challenge. Future biomarker-guided clinical trials are essential to determine the clinical relevance and to establish precision medicine strategies targeting the iron–inflammation crosstalk in CRC. Full article