Effective CD4+ T cell responses are essential for controlling Mycobacterium tuberculosis (Mtb), but they fail to achieve sterilizing immunity in infected lungs. In mouse models of Mtb infection, single-cell transcriptomic profiling identified a dominant population of OX40+ CD4+ T cells that emerged during Mtb infection yet exhibited impaired effector differentiation. This dysfunction was linked to defective co-stimulatory signaling, corresponding to persistently low OX40 ligand (OX40L) expression on antigen-presenting cells. Therapeutic activation of OX40 restored CD4+ T cell functionality, expanded protective clonotypes, and reduced pulmonary bacterial burden in vivo. These effects required intact CD40-CD40L interactions to sustain OX40 expression and promote T cell differentiation, and were critically dependent on interferon (IFN)-γ signaling for antimicrobial activity. CD40L blockade abolished the immunotherapeutic benefits of OX40 stimulation, revealing a cooperative CD40-OX40 axis that orchestrates protective immunity in tuberculosis. These findings identify impaired co-stimulatory signaling as a central mechanism of CD4+ T cell dysfunction during chronic infection and highlight this axis as a target for host-directed immunotherapy in tuberculosis.

Cutaneous wound healing is a complex, tightly regulated biological process encompassing four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. While acute wounds typically progress through these stages in a coordinated manner, various pathological conditions, including diabetes mellitus and microbial infections, can impair this process, resulting in chronic, non-healing wounds. A sustained inflammatory phase characterizes chronic wounds and is commonly associated with systemic immune dysregulation. Emerging evidence show that regulatory T cells (Tregs) are critical modulators of tissue homeostasis and regeneration. Tregs exert their effects through the expression of immunoregulatory molecules and the secretion of anti-inflammatory cytokines, facilitating the resolution of inflammation, supporting angiogenesis, and promoting tissue repair. In the context of cutaneous wounds, skin-resident Tregs interact with both immune and non-immune cells, contributing to the restoration of barrier integrity. This review highlights the multifaceted roles of Tregs in cutaneous wound healing, with a particular emphasis on their contributions to the inflammatory and proliferative phases, including vascularization and regulation of fibroblasts. Furthermore, emerging therapeutic strategies targeting Tregs to modulate their function in chronic wound settings are discussed. These insights underscore the potential of Tregs as novel immunotherapeutic targets for enhancing wound repair and regeneration in chronic and diabetic wound pathologies.

The rising concern of antimicrobial resistance, coupled with the continually challenging management of complicated diseases such as cancer, has provided momentum toward precision molecular medicine. This review provides an overview of bacteriophage enabled strategies encompassing both conventional antibacterial applications and advanced bioengineered delivery systems. Recent advances in phage therapy include the use of tailored phage formulations, phage immobilization approaches and phage antibiotic combinations to achieve targeted bacterial lysis particularly against multidrug-resistant pathogens and biofilm-associated infections. Beyond their intrinsic antibacterial activity, phages can be genetically and chemically engineered as nanoscale scaffolds. Phage display technologies enable the incorporation of targeting ligands for selective binding to specific tissues including tumor cells. Furthermore, phage capsids can be modified to encapsulate and deliver diverse therapeutic payloads such as small-molecule drugs, nucleic acids and gene-editing systems such as CRISPR–Cas, thereby expanding their utility beyond infectious diseases. The integration of phage biology with nanobiotechnology positions these viral platforms at the forefront of next generation therapeutics. Engineered phages have demonstrated potential as precision delivery vectors for cytotoxic agents, immunomodulators and genetic material with improved specificity and reduced off-target effects. Emerging strategies including phage antibiotic conjugates and enzyme functionalized phages further enhance therapeutic efficacy and facilitate penetration of physiological barriers. Collectively, phage-based platforms represent a versatile and transformative approach with significant implications for the treatment of infectious, oncologic and genetic disorders, supporting the advancement of targeted and personalized medicine.

Autoimmune and inflammatory diseases are characterized by dysregulated T cell-mediated immune responses leading to tissue damage. Despite therapeutic advancements, patients remain resistant to treatment, highlighting the urgent need for alternative therapeutic strategies. Here, we identified neuritin (NRN), an immunosuppressive molecule, capable of restraining effector CD4+ T cell responses and mitigating autoimmune and inflammatory diseases. NRN is downregulated in CD4+ T cells of rheumatoid arthritis (RA) patients, driving T cell-mediated autoimmune pathology. Nrnfl/flCD4Cre mice exacerbate both experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, characterized by regulatory T cell (Treg) depletion and expansion of interferon (IFN)-γ+ and interleukin (IL)-17+ pro-inflammatory cells. Mechanistically, NRN selectively binds to cannabinoid receptor 2 (CB2), but not to CB1, specifically through its threonine residues at positions T78 and T81. Meanwhile, mice lacking CB2 (CB2-/- or CB2fl/flCD4Cre) exhibit worsened colitis, with an increased IFN-γ+ and IL-17+ cells, mirroring the Nrnfl/flCD4Cre phenotype. T cell-specific Nrn knockin (NrnKI/KICD4Cre) or exogenous NRN administration ameliorated disease severity in multiple autoimmune models, including DSS-induced colitis, IMQ-induced psoriasis, and collagen-induced arthritis, by promoting Treg expansion and suppressing IFN-γ+ and IL-17+ pro-inflammatory cells. However, these protective effects of NRN were abolished in CB2-deficient mice. Overall, NRN is an immunosuppressive molecule with therapeutic potential in autoimmune and inflammatory diseases.

The advancement of synthetic biology and the rise of antimicrobial resistance have led to the development of bacteriophage therapy for more than antibacterial applications. This review focuses on applications to multidrug-resistant infections, biofilm diseases, cancer research, veterinary medicine and animal production. Recent research suggests phages can be used in combination with antibiotics to enhance treatment of large multidrug resistant pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. This could also help to restore antibiotic sensitivity by making bacteria change resistance related structures or mechanisms. Despite this, there are several challenges for the use of phage therapy prior to its widespread clinical application, including phage resistance, difference in patient response, unknown pharmacokinetic parameters, immune issues, and unclear regulatory guidelines. Additionally, in some cases, phages could also play a role in horizontal gene transfer, raising further safety concerns. Beyond antimicrobial therapy, phage display platforms derived from M13, T7 and λ phages have enabled the identification of tumor-targeting peptides, the development of immunomodulatory constructs, and targeted delivery of therapeutic molecules. Over 100 clinical cases and 44 registered trials support the generally favorable safety profile of personalized phage therapy, and highlight the need for better treatment standardization, controlled clinical evaluation, and better regulatory processes. Additionally, engineered phages expressing biofilm degrading enzymes represent promising tools for disrupting matrix-embedded bacterial communities associated with chronic infections and medical devices. In summary, CRISPR-based engineering and genome refactoring highlight the potential of phage-based therapeutics as complements to conventional antimicrobial therapy, although their broader use depends on overcoming biological, clinical, and regulatory challenges.

The Hippo signaling pathway is a fundamental regulator of organ growth, tissue regeneration, and cellular homeostasis, with far-reaching implications in cancer biology and immunology. Dysregulation of this pathway, particularly through its downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), is closely associated with oncogenic transformation and the establishment of an immunosuppressive tumor microenvironment (TME). This review discusses current knowledge on the multifaceted roles of Hippo signaling in cancer, focusing on its interactions with T cell-mediated immunity and mechanisms of tumor immune regulation. Aberrant YAP/TAZ activation enhances cancer cell proliferation, remodels the TME, and reprograms immune responses to favor tumor growth and immune evasion. The review explores how modulation of Hippo pathway components influences both tumor progression and immune cell function, highlighting its central role in shaping anti-tumor immunity. Furthermore, the therapeutic potential of targeting YAP/TAZ signaling is discussed in the context of advancing precision medicine and improving immunotherapeutic outcomes. Collectively, this work highlights the Hippo signaling cascade as both a key driver of tumorigenesis and a crucial regulator of immune modulation. A comprehensive understanding of its molecular interactions with T cells and the TME will support the development of innovative YAP/TAZ-targeted strategies that integrate molecular signaling and immune modulation, offering new directions for effective cancer therapy.

The acidic tumor microenvironment (TME) promotes immune escape by suppressing T-cell function, creating a major barrier to immunotherapy. Here, acidic pH-mediated impairment of T cell responses via the proton-sensing receptor GPCR68 is identified, whereas mild extracellular alkalinization counteracts this pathway to restore T cell effector function. GPCR68 acts as a negative regulator of T cell–driven anti-tumor immunity, as evidenced by the enhanced cytokine production (IFN-γ, TNF-α) and suppressed tumor growth in T cell–specific GPCR68 knockout mice (GPCR68fl/flCD4Cre). Thus, a borate-optimized local tumor therapy (BOLT) strategy is engineered to target GPCR68, based on alkali-metal-ion-modulated borate bioactive glass, which is integrated, spatiotemporally multiple responsive, and locally injectable. BOLT combats tumors dually by potentiating T cell immunity and inducing tumor ferroptosis. It alleviates acid suppression of T cells via GPCR68 inhibition and PI3K/AKT/mTOR signal activation, while promoting ferroptosis through the upregulation of Duox1/ROS and suppresseion of NRF2/SLC7A11/GPX4 axis. Therapeutically, BOLT synergizes with anti-CTLA4 blockade to overcome immunotherapy suppression and markedly enhances tumor immunity. These findings establish GPCR68 as a critical pH-sensing regulator of T-cell function and a therapeutic target for pH-based immunomodulation, and propose BOLT as a translational strategy for “alkaline intervention therapy” to potentiate immunotherapy.

Microglia, essential in the central nervous system (CNS), were historically considered absent from the peripheral nervous system (PNS). Here, we show a PNS-resident macrophage population that shares transcriptomic and epigenetic profiles as well as an ontogenetic trajectory with CNS microglia. This population (termed PNS microglia-like cells) enwraps the neuronal soma inside the satellite glial cell envelope, preferentially associates with larger neurons during PNS development, and is required for neuronal functions by regulating soma enlargement and axon growth. A phylogenetic survey of 24 vertebrates revealed an early origin of PNS microglia-like cells, whose presence is correlated with neuronal soma size (and body size) rather than evolutionary distance. Consistent with their requirement for soma enlargement, PNS microglia-like cells are maintained in vertebrates with large peripheral neuronal soma but absent when neurons evolve to have smaller soma. Our study thus reveals a PNS counterpart of CNS microglia that regulates neuronal soma size during both evolution and ontogeny.

BackgroundCancer immunotherapy has shown promising results in the clinic, but it faces great challenges such as low response rates and low efficacy in solid tumors. c-Rel, a member of the nuclear factor (NF)-κB family, is a newly described immune checkpoint for myeloid-derived suppressor cells (MDSCs), which contribute to the formation of immune-suppressive tumor microenvironment and resistance to cancer immunotherapy. How to selectively target myeloid c-Rel for the treatment of cancer is not well established. In this study, we investigated the feasibility and efficacy of knocking down myeloid c-Rel with siRNA-loaded peptide-based nanoparticles as a new cancer immunotherapy strategy.MethodsThe knockdown of c-Rel gene by the siRNA-loaded peptide nanoparticles was confirmed on MDSCs in vitro and in vivo. The effects of c-Rel silencing on cell number and immune suppressive function of the murine bone marrow-derived MDSCs were then investigated. To evaluate the anti-tumor efficacy of the c-Rel siRNA loaded nanoparticles, female C57BL/6 mice with subcutaneous B16 tumor were treated with PBS, c-Rel siRNA loaded nanoparticles, control siRNA loaded nanoparticles or empty nanoparticles. The tumor growth and body weight of mice were monitored, and the numbers and immune activities of tumor infiltrated immune cells in different groups were analyzed at the end of the experiment. The immune function of MDSCs isolated from tumor bearing mice received different treatments were further investigated ex vivo by T cell proliferation assays.ResultsThe c-Rel siRNA nanoparticles significantly reduced c-Rel expression in MDSCs, diminished both the number and immune suppressive function of MDSCs, and enhanced intratumor CD8+ T cell responses. Significantly reduced tumor growth was observed in mice treated with the c-Rel siRNA nanoparticles compared to control mice.ConclusionOur data indicates that peptide-based nanoparticles can be successfully utilized to target the myeloid immune checkpoint c-Rel for the treatment of cancer.

Regulatory T cells (Treg cells) are a specialized subset of CD4'T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance. The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4'CD25' suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function; together with landmark FOXP3 genetic discoveries by Mary E. Brunkow and Fred Ramsdell, these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine. Under normal physiological conditions, FOXP3' Treg cells restrain autoreactive lymphocytes, prevent excessive inflammation, and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines, thereby protecting tissues from immune-mediated damage. Disruption of Treg abundance, stability, or suppressive capacity can therefore lead to immune dysregulation and disease. Over the past two decades, Treg cells have become a major focus of immunology because their roles are highly context-dependent. In autoimmune and chronic inflammatory diseases, impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury, supporting therapeutic approaches designed to enhance Treg cell number, stability, and suppressive potency. In contrast, many cancers exploit Treg cells by promoting their expansion, activation, and recruitment into the tumor microenvironment (TME), where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function, limiting dendritic cell activation, and fostering immune escape. In both settings, immune checkpoint pathways critically influence Treg cell biology. Beyond PD-1/PD-L1 and CTLA-4, emerging checkpoints and costimulatory receptors, including TIGIT, TIM-3, LAG-3, and OX40, modulate Treg cell generation, stability, and suppressive functions, thereby shaping the balance between tolerance and immunity. Meanwhile, immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors; lipid utilization and mitochondrial programs, among other metabolic axes, enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments, while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner. In this review, we summarize the discovery and defining biological features of Treg cells, highlight core suppressive mechanisms and regulatory circuits, and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion. We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease, or selectively depleting, functionally inhibiting, and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy. Overall we discuss how deeper insight into Treg heterogeneity, checkpoint control, and immunometabolic regulation may enable more precise Treg cell-directed interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.

Inflammatory bowel disease (IBD) encompasses two main conditions: Crohn's disease and ulcerative colitis. The role of foodborne pathogens, often transmitted through contaminated food, is a subject of ongoing research regarding their potential involvement in IBD. The most common foodborne pathogens S. typhimurium usually causes intestinal inflammation in the intestines of both humans and cattle, known as enterocolitis. Phage therapy shows promise in treating Salmonella-induced colitis due to its highly specific targeting of bacteria. Here, we demonstrated the efficacy of phage therapy in a murine model of Salmonella-induced colitis. In mice, Salmonella administration exacerbated colitis severity, as evidenced by reduced colon length and elevated production of inflammatory cytokines. Comprehensive metabolomic investigations demonstrated that treatment with a Salmonella-specific novel phage FPSP6 effectively mitigated colitis induced by Salmonella. This therapeutic approach effectively reduced intestinal inflammation, increased CD4+ T-cell levels and decreased cytokine expression, demonstrating its potential efficacy and safety for treating Salmonella-induced colitis. This study, the first to verify the effectiveness and immunomodulatory mechanism of FPSP6, indicates that phage therapy targeting the gut microbiota is a viable alternative to antibiotics, connecting phage therapy, immune regulation, and microbial dynamics in the context of intestinal inflammation caused by foodborne pathogens.

Objective Neuroinflammation plays a crucial role in both the onset and progression of ischemic stroke, exerting a significant impact on the recovery of the central nervous system. Excessive neuroinflammation can lead to secondary neuronal damage, further exacerbating brain injury and impairing functional recovery. As a result, effectively modulating and reducing neuroinflammation in the brain has become a key therapeutic strategy for improving outcomes in ischemic stroke patients. Among various approaches, targeting immune regulation to control inflammation has gained increasing attention. This study aims to investigate the role of in vitro induced regulatory T cells (Treg cells) in suppressing neuroinflammation after ischemic stroke, as well as their potential therapeutic effects. By exploring the mechanisms through which Tregs exert their immunomodulatory functions, this research is expected to provide new insights into stroke treatment strategies. Methods Naive CD4+ T cells were isolated from mouse spleens using a negative selection method to ensure high purity, and then they were induced in vitro to differentiate into Treg cells by adding specific cytokines. The anti-inflammatory effects and therapeutic potential of Treg cells transplantation in a mouse model of ischemic stroke was evaluated. In the middle cerebral artery occlusion (MCAO) model, after Treg cells transplantation, their ability to successfully migrate to the infarcted brain region and their impact on neuroinflammation levels were examined. To further investigate the role of Treg cells in stroke recovery, the changes in cytokine expression and their effects on immune cell interactions was analyzed. Additionally, infarct size and behavioral scores were measured to assess the neuroprotective effects of Treg cells. By integrating multiple indicators, the comprehensive evaluation of potential benefits of Treg cells in the treatment of ischemic stroke was performed. Results Treg cells significantly regulated the expression levels of both pro-inflammatory and anti-inflammatory cytokines in vitro and in vivo, effectively balancing the immune response and suppressing excessive inflammation. Additionally, Treg cells inhibited the activation and activity of inflammatory cells, thereby reducing neuroinflammation. In the MCAO mouse model, Treg cells were observed to accumulate in the infarcted brain region, where they significantly reduced the infarct size, demonstrating their neuroprotective effects. Furthermore, Treg cell therapy notably improved behavioral scores, suggesting its role in promoting functional recovery, and increased the survival rate of ischemic stroke mice, highlighting its potential as a promising therapeutic strategy for stroke treatment. Conclusion In vitro induced Treg cells can effectively suppress neuroinflammation caused by ischemic stroke, demonstrating promising clinical application potential. By regulating the balance between pro-inflammatory and anti-inflammatory cytokines, Treg cells can inhibit immune responses in the nervous system, thereby reducing neuronal damage. Additionally, they can modulate the immune microenvironment, suppress the activation of inflammatory cells, and promote tissue repair. The therapeutic effects of Treg cells also include enhancing post-stroke recovery, improving behavioral outcomes, and increasing the survival rate of ischemic stroke mice. With their ability to suppress neuroinflammation, Treg cell therapy provides a novel and effective strategy for the treatment of ischemic stroke, offering broad application prospects in clinical immunotherapy and regenerative medicine.

Regulatory T cells (Tregs) and effector T cells play critical roles in tumor immunity, with Tregs suppressing immune responses and contributing to an immunosuppressive tumor microenvironment (TME). Neuritin-1 (Nrn), a neuropeptide, has been identified to enhance Treg expansion. However, its role in T cell biology and tumor development remains unclear. We demonstrated that Nrn is highly expressed in the in-vitro-induced Tregs (iTregs). Functionally, Nrn promoted iTreg differentiation in a dose-dependent manner, while Nrn deletion or anti-Nrn antibody treatment significantly inhibited iTreg differentiation. Additionally, Nrn suppressed IL-2 transcription and secretion in T cells, impairing T cell activation and pro-inflammatory cytokine production. Treg-specific Nrn knockout mice exhibited reduced B16 melanoma tumor growth, decreased Treg infiltration, and increased effector T cell infiltration. Conversely, overexpression of Nrn accelerated B16 melanoma tumor progression by enhancing Treg-mediated suppression. Importantly, we developed the first anti-Nrn antibody, which effectively reduced tumour growth, decreased Treg infiltration, and enhanced effector T-cell activity. Importantly, anti-Nrn synergistically worked with anti-PD1 and improved the anti-PD1 response by reducing Tregs and increasing effector function in tumor-infiltrated T cells, resulting in enhanced tumor regression. Our findings identify Nrn as a critical regulator of Treg differentiation and effector T cell suppression, contributing to tumor progression. Targeting Nrn alone or combined with anti-PD1 therapy represents a promising strategy to enhance anti-tumor immunity.

Lung cancer is the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Immune checkpoint inhibitors (ICIs) represented by anti-programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) have emerged as a promising frontier in cancer treatment, effectively extending the survival of patients with NSCLC. However, the efficacy of ICIs exhibits significant variability across diverse patient populations, with a substantial proportion showing poor responsiveness and acquired resistance in those initially responsive to ICIs treatments. With the advancement of nanotechnology, nanoparticles offer unique advantages in tumor immunotherapy, including high permeability and prolonged retention(EPR) effects, enhanced drug delivery and stability, and modulation of the inflammatory tumor microenvironment(TME). This review summarizes the mechanisms of resistance to ICIs in NSCLC, focusing on tumor antigens loss and defective antigen processing and presentation, failure T cell priming, impaired T cell migration and infiltration, immunosuppressive TME, and genetic mutations. Furthermore, we discuss how nanoparticles, through their intrinsic properties such as the EPR effect, active targeting effect, shielding effect, self-regulatory effect, and synergistic effect, can potentiate the efficacy of ICIs and reverse resistance. In conclusion, nanoparticles serve as a robust platform for ICIs-based NSCLC therapy, aiding in overcoming resistance challenges.

Aging of the fetal membranes participates in labor onset. However, the underlying mechanism is poorly understood. Here, we identify that the classical secretory protein S100 calcium-binding protein A9 (S100A9), upon de-phosphorylation at Thr 113, translocates to the nuclei of amnion fibroblasts of the human fetal membranes, where S100A9 causes heterochromatin erosion via segregation of heterochromatin maintenance proteins, resulting in Long Interspersed Nuclear Element-1 (LINE1) de-repression at parturition. Increased LINE1 retrotransposition further activates the type I interferon response via the cGAS-STING pathway, thereby leading to amnion fibroblast senescence with consequent increased secretion of components associated with senescence-associated secretory phenotype. Mouse studies show that intra-amniotic injection of vector specifically expressing S100A9 in the nucleus induces preterm birth along with LINE1 de-repression and increased cellular senescence in the fetal membranes, which is blocked by inhibition of LINE1 reverse-transcription. Together, these findings highlight that nuclear-translocated S100A9 acts as a heterochromatin disruptor to de-repress LINE1 which subsequently triggers amnion fibroblast senescence at parturition.

The effects of nicotine on aging-related motor and cognitive decline remain controversial due to limited empirical evidence. Here, mice are permitted to orally consume nicotine over a 22-month period and observed attenuated motor decline without pathological alterations in major metabolism-related peripheral organs or immune system dysfunction. Multi-organ metabolomic profiling and network analysis of aged mice (24 months old) identified nicotine-responsive pathways related to glycolipid metabolism and energy homeostasis. Dynamic gut microbiota profiling via series expression miner-based longitudinal analysis reveals that nicotine consumption preserved microbiota composition and altered microbial-derived metabolites associated with the sphingolipid pathway, known to regulate age-related muscle dysfunction and sarcopenia. Assays in aged mice and C2C12 cells confirmed that nicotine regulates sphingolipid turnover, particularly via sphingomyelin synthases and neutral sphingomyelinases, to enhance nicotinamide adenine dinucleotide availability and energy metabolism. These metabolic adaptations correlated with reduced ceramide accumulation and improved motor function. Behavior-Metabolome Age (BMAge) score confirmed a biologically younger phenotype in the nicotine-treated mice. Together, these findings suggest that life-long oral nicotine consumption reprograms aging-associated metabolism through regulation of systemic sphingolipid homeostasis, conferring resilience against age-related motor decline.

Diabetes and metabolic disorders represent a global health crisis driven by complex interactions between metabolic, immune, and microbial networks. Beyond their metabolic derangements- hyperglycemia, insulin resistance, and low-grade systemic inflammation-these disorders are now recognized to exist at an immunometabolic interface profoundly influenced by infectious agent The bidirectional relationship between infections and metabolic dysregulation highlighting how acute and chronic infections contribute to insulin resistance, β-cell dysfunction, and systemic inflammation, while metabolic dysregulation impairs immune competence, predisposing individuals to recurrent and severe infections. Pathogens such as Helicobacter pylori Staphylococcus aureus, Escherichia coli, SARS-CoV-2, and hepatitis viruses, alter host metabolic signaling through inflammatory, mitochondrial, and hormonal pathways, reshaping glucose and lipid homeostasis. In turn, diabetic immune impairment amplifies susceptibility to pneumonia, urinary tract infections, and chronic wound infections, reinforcing a pathogenic feedback loop. Emerging therapeutic strategies including nanotechnology enabled, therapeutics, gene, and stem cell based interventions and next-generation incretin agonists- including tirzepatide and CagriSem offer promising avenues to restore both metabolic balance and immune resilience. Additionally, foundational strategies such as lifestyle modifications, medical nutrition therapy, and vaccination remain essential components of disease control. Understanding infections as dynamic modulators of metabolic homeostasis reframes diabetes not merely as an endocrine disorder, but as a systemic immunometabolic disease. This review synthesizes current evidence on infection induced metabolic syndrome, immune impairments, and innovative therapeutic strategies to guide future precision interventions at the infection-metabolism interface.

Meeting the demand for efficient photosensitizers in photodynamic therapy (PDT), a series of iridium(iii) complexes decorated with silicane-modified rhodamine (Si-rhodamine) was meticulously designed and synthesized. These complexes demonstrate exceptional PDT potential owing to their strong absorption in the near-infrared (NIR) spectrum, particularly responsive to 808 nm laser stimulation. This feature is pivotal, enabling deep-penetration laser excitation and overcoming depth-related challenges in clinical PDT applications. The molecular structures of these complexes allow for reliable tuning of singlet oxygen generation with NIR excitation, through modification of the cyclometalating ligand. Notably, one of the complexes (4) exhibits a remarkable ROS quantum yield of 0.69. In vivo results underscore the efficacy of 4, showcasing significant tumor regression at depths of up to 8.4 mm. This study introduces a promising paradigm for designing photosensitizers capable of harnessing NIR light effectively for deep PDT applications.

Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.

Lysosomes are acidic membrane-bound organelles that aid digestion, excretion, and cell renewal. The lysosomal membranes are essential for maintaining lysosomal functions and cellular homeostasis. In this work, we developed a molecular "NOR" logic gate, SIATFluor-580L, by introducing malachite green into the spirocyclic rhodamine. SIATFluor-580L requires restriction of molecular rotation of the malachite green motif (Input 1, tight membrane structure) and a large amount of H+ ions to convert the spirocyclic rhodamine into the zwitterionic form (Input 2, acidic environment) to produce a fluorescent product (Output), providing a fluorogenic probe to visualize the lysosomal membrane dynamics in living cells with subdiffraction resolution by using HyVolution (also known as Lightning), an unconventional and inexpensive super-resolution imaging approach based on a basic confocal optical system.