Browse Articles

Respiratory viral infections prime accelerated lung cancer growth 2254615

Abstract Introduction The COVID-19 pandemic has highlighted long-term health concerns of viral pneumonia, yet its potential impact on cancer development and growth remains poorly understood. Methods Retrospective clinical analysis and multiple mouse lung cancer models. Results Retrospective clinical analysis revealed that patients hospitalized with COVID-19 exhibited increased lung cancer incidence. Using multiple murine lung cancer models, we show that prior severe respiratory viral infections accelerated tumor growth and reduced survival. Mechanistically, prior viral pneumonia epigenetically remodeled the lung to establish a pro-tumor microenvironment, including the local accumulation of SiglecFhi tumor-associated neutrophils, a transcriptionally reprogrammed, immunosuppressive population whose signature predicted poor prognosis in human lung adenocarcinoma. In parallel, epithelial compartments exhibited altered differentiation trajectories, with persistence of injury-associated alveolar intermediates positioned along tumorigenic lineages. We observe sustained chromatin remodeling at key cytokine loci in immune and structure cells, linking inflammatory memory to persistent immune suppression. Therapeutically, combined inhibition of neutrophil recruitment via CXCR2 and PD-L1 signaling restored CD8+ T cell infiltration and suppressed tumor growth. Conclusion Our findings establish a direct causal relationship between viral pneumonia, including COVID-19, and lung tumorigenesis, highlighting the urgent need to monitor survivors for elevated cancer risk and to develop targeted interventions and therapies aimed at preventing potential cancer bursts in COVID-19 convalescents. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Inverse Relationship Between T and B cell Affinity in the Germinal Center Reaction 2267583

Abstract Introduction Germinal centers are the sites of antibody affinity maturation and diversification. Both processes are governed by T follicular helper cells (TFH) that recognize and select B cells based on their ability to display cognate peptide-MHCII complexes (p-MHCII). As higher-affinity B cells internalize and present more antigen-derived peptides, the amount of cognate p-MHCII displayed by a B cell is proportional to its affinity toward the immunogen. Although the mechanisms that regulate antibody affinity maturation are well characterized, the regulation of antibody diversification is less understood. We hypothesize that TFH, the cellular conductors of GC B cell selection, may play a role. Methods Here, we examined how TCR sensitivity, shapes thresholds for GC B cell selection, using peptide variants that tune T cell activation in vivo and pharmacological modulation of TCR signaling. Through these complementary approaches, we uncover an inverse relationship between T and B cell affinities within the germinal center reaction. Results Here we report, that TFH are selected for expression of higher-avidity TCRs, preceding the terminal phase of the response, which is dominated by functionally distinct T follicular regulatory (TFR) . This enhanced sensitivity of TFH TCRs, effectively lowers the threshold for B cell selection, enabling the recruitment and maintenance of a boarder spectrum of B cell affinities. Conclusion Together are findings highlight how selection for higher affinity TFH shape the antibody landscape by lowering selection thresholds for B cell selection enabling recruitment and support of more diverse antibody affinities, and provides a new conceptual framework for designing vaccines that calibrate T cell help to steer affinity maturation toward protective antibody responses Funding Source Branco Weiss Fellowship Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Growth Arrest-Specific 6-Mediated Efferocytosis Reveals Bidirectional Tolerogenic Crosstalk Between DCs and T Cells 2309074

Abstract Introduction Efferocytosis is a key driver of immune tolerance, yet the mechanisms linking apoptotic cell clearance to tolerogenic antigen presentation remain unclear. Existing models suggest that tolerance relies on immunological silence through reduced antigen presentation on MHC. Recognizing the role of GAS6 in facilitating efferocytic antigen uptake, we engineered GAS6-OVA (GO), fusing bridge protein GAS6 to ovalbumin to dissect antigen-specific tolerance mechanisms in both APCs and T cells. Methods Variants of GO were expressed in HEK293F cells and purified by chromatography. BMDCs were antigen-pulsed ±LPS and co-cultured with OT-I or OT-II T cells. Flow cytometry assessed phenotypes. In vivo, adoptively transferred OT cells were tracked following GO/OVA treatment and CFA-OVA challenge. Wild-type mice were pretreated with GO or controls prior to induction of allergic airway inflammation. Results GO exhibited PS-specific binding and enhanced DC uptake. Instead of dampening presentation, GO-pulsed BMDCs upregulated MHC-I and -II, driving robust proliferation of OT-I and -II cells. CD8+ T cells displayed a phenotype resembling terminal exhaustion (PD-1+TIM-3+TOX+), while CD4+ T cells were enriched for Tregs displaying phenotypic signs of robustness (Helios+CD73+FR4hi). Crucially, the tolerogenic phenotype of DCs did not emerge immediately; DC expression of PD-L1 and TAM receptors increased only after engagement with antigen-specific T cells. These signatures of tolerance persisted under LPS stimulation. In vivo, GO reduced antigen-specific T cell recovery, enriched Tregs, and prevented allergic airway pathology including IgE and mucus hypersecretion. Conclusion GAS6-mediated efferocytosis drives bidirectional tolerogenic programming where APCs and T cells reciprocally reinforce tolerance. Enhanced, not reduced, antigen presentation accompanies tolerance-associated phenotypes. This self-reinforcing circuit may enable durable antigen-specific therapies for allergies, autoimmunity, and transplant rejection. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Neuroinflammation in the mouse striatum induced by aging and excitotoxic damage: possible role of S100B protein, RAGE receptor and Mast Cells 2256468

Abstract Introduction Aging is importantly associated to the development of neurodegenerative diseases, including those affecting the motor control and striatum function. It is clear the need to study those changes affecting that brain nucleus during aging, such as the neuroinflammatory phenomenon. This project was directed to evaluate the possible age-related changes in the inflammatory response against an excitotoxic stimulus through the evaluation of the RAGE/S100B axis, exploring at the same time the role of mast cells (MC), one of the less studied cell elements in the brain. Methods We used mice of different ages (16, 64 and 80 weeks), in which we induced an excitotoxic response by the unilateral administration of the NMDA agonist quinolic acid (QA), directly into the striatum of WT (C57BL6/J) and mast cell-deficient c-Kit Wsh/Wsh (Wsh) mice. After QA administration we measured the neurological damage through the evaluation of ipsilateral turns induced by apomorphine. Then, the integrity of perineuronal nets (PNNs), as well as the presence of different inflammatory markers like S100B protein, RAGE receptor and different cytokines was assessed. Results Results obtained to date demonstrate a differential expression of inflammatory components between C57 and Wsh mice after QA administration, with an increase in RAGE receptor in young male mice striatum. This parameter correlates with a major PNNs degeneration and higher levels in the expression of inflammatory cytokines. A reduction in the expression of components of the inflammatory response was observed in aging. Conclusion MC seem to be central components in the magnification of the neuroinflammatory response in the excitotoxic QA-induced model. The absence of response in MC-deficient mice results in a decreased inflammation and less neuronal damage. Also, aged mice display a reduced inflammatory capacity that may be related with the brain frailty observed in aging. Funding Source Grant CONAHCYT Grant No. 51488 Topic Categories Neuroimmunology (NEUR)

A Whole Blood Fixation Strategy for Scalable Paired Single Cell Whole Transcriptome and Immune Receptor Profiling 2310144

Abstract Introduction Single cell RNA sequencing (scRNA-seq) is a foundational technology in immunology, enabling high-resolution analysis of immune cell states, activation programs, and clonal diversity that cannot be resolved by bulk methods. However, broad translational adoption is limited by reliance on fresh peripheral blood mononuclear cell (PBMC) isolation shortly after collection. This process requires specialized equipment, trained personnel, and rapid processing, which are often infeasible in decentralized or multi-site settings, limiting scalability and access to single cell technologies. Methods We developed a whole blood fixation and stabilization method optimized for combinatorial barcoding-based scRNA-seq, enabling paired whole transcriptome and T cell receptor (TCR) analysis. The workflow preserves cellular integrity and RNA quality and uses dual-primed reverse transcription with poly(dT) and random hexamer primers for unbiased RNA capture. Fixed whole blood samples from individuals with systemic lupus erythematosus, rheumatoid arthritis, type 2 diabetes, and healthy donors were analyzed. Fixed whole blood data from healthy donors were compared to freshly isolated PBMCs from matched donors. Results Fixed whole blood profiling robustly recovered major immune cell populations and preserved relative cell type proportions. Disease samples recapitulated known immune activation and inflammatory transcriptional programs across immune subsets. Paired TCR profiling revealed shifts in TCR clonotypes and gene expression. Samples processed via whole blood fixation showed strong concordance in gene expression profiles relative to donor-matched freshly isolated PBMCs. Conclusion This platform enables scalable, unbiased paired single-cell transcriptome and immune receptor profiling directly from fixed whole blood. By simplifying collection while preserving immune cell composition, activation states, and clonal features, this approach expands access to single-cell technologies for large-scale immunology studies. Funding Source n/a Topic Categories Technological Innovations in Immunology (TECH)

Engineering bioluminescent bacteria for in vivo immune response tracking in D. melanogaster 2333028

Abstract Introduction Immune activation is a tightly controlled process, as overactivation leads to autoimmunity, while underactivation allows bacteria to grow unchecked. Genetically identical D. melanogaster, which rely solely on an innate immune response, infected with the same number of bacteria will die at varying times due to random variation in pathogen growth and immune response. Through indirect observation, previous research suggests that variation in survival arises from variation in the onset of the immune response in the fly. However, how exactly bacterial growth and immune response determine the outcome of an infection has yet to be observed due to the difficulty of obtaining individual and real-time data. Methods Dilution plating can estimate bacterial growth but loses the nuance of individual immunity over time. To continuously track individual flies, we generated bioluminescent bacteria using the iLux plasmid, which has a broad host range and confers auto-bioluminescence. As a model, we used P. rettgeri, a gram-negative bacteria that is moderately lethal to flies, leading to a variety of infection outcomes.We tracked P. rettgeri growth in infected flies in a high-throughput manner as a proxy for fly immune function. Results Flies individually housed in a 96-well plate and injected with bioluminescent P. rettgeri were imaged every 10-30 minutes. Among these flies, three outcomes were observed: clearance of the infection to undetectable levels, stabilization of infection at a chronic load, or death from an uncontrolled infection. Conclusion Using D. melanogaster and bioluminescent P. rettgeri, we can observe host-pathogen interactions in a model system ideal for studying the conserved features of innate immunity in the absence of an adaptive immune response. In future work we will image immune reporter flies injected with bioluminescent bacteria, tracking how the bacterial signal changes in response to directly observable immune activation and generating models for the determinants of infection outcome. Funding Source This research was supported by a Kilachand Fellowship funded by the Boston University Multicellular Design Program Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

Turning Unpredictable Biomolecule Adsorption to Controlled Corona Formation: Focus on Carbon Nanomaterials (Adv. Mater. 46/2026)

Short‐Wave Infrared Organic Photodetectors With Ultralow Dark Current Density Under Biased Operating Conditions

ABSTRACT Commercial photodetectors integrated on readout circuits typically operate under bias voltage, necessitating low dark current density ( J d ) to achieve high detectivity. However, suppressing J d remains a critical challenge for organic photodetectors (OPDs), particularly those operating in the short‐wave infrared (SWIR) region. Herein, we report SWIR‐OPDs that achieve ultralow J d under high bias voltage by developing a narrow bandgap p‐type polymer as the SWIR absorber, thereby establishing an alternative material platform for high‐performance SWIR‐OPDs. The new polymer PDCBT‐DTO2F adopts a push‐pull architecture comprising quaterthiophene donor units and 5,6‐dicyano‐2,1,3‐benzothiadiazole acceptor moieties. Substituting the alkyl chains on quaterthiophene units with alkoxy chains significantly enhanced the intramolecular charge transfer effect and backbone coplanarity. This modification simultaneously yielded intense SWIR absorption, high crystallinity, reduced trap density, and low energetic disorder. Through extensive device optimization, the SWIR‐OPD based on PDCBT‐DTO2F exhibited J d as low as 15.6 nA cm – 2 under −2 V and 58.1 nA cm −2 even under −5 V. Consequently, a detectivity of 1.04 × 10 12 Jones was realized at 1100 nm under −2 V bias, ranking among the best performance for SWIR‐OPDs operating under reverse bias.

Zwitterionic poly (amino acid methacrylate) brushes functionalized dendritic mesoporous silica nanoparticles in layer-by-layer assembled membranes for selective Ion separation

The multifaceted nature of digital distraction in contemporary learning environments 2256303

Abstract Introduction The rapid integration of digital technologies into daily life has transformed the educational landscape, providing unprecedented access to information and learning tools. However, this digital shift has also introduced a major challenge: digital distraction. Students today are increasingly prone to interruptions from smartphones, social media, instant messaging, and other online platforms during class time. These distractions can break attention, lower cognitive engagement, and hinder academic success. Methods We at Chicago State University used appropriate surveillance methods, such as direct observation, digital monitoring, biometric sensors, and self-reporting tools. Ensured ethical practices by obtaining informed consent, protecting privacy, and maintaining transparency. Used tools such as LMS analytics, screen-monitoring software, and video analysis platforms to collect data. Analyzed the data using qualitative or quantitative methods. Results We examined how constant connectivity and the lure of digital entertainment compete with academic tasks, leading to decreased concentration and poorer retention of instructional content. Data show that even glances at mobile devices during class can interrupt the learning process, as the brain needs time to refocus after each distraction. Additionally, the habitual use of multiple digital platforms fosters a culture of multitasking, which has been shown to impair deep learning and critical thinking. The current study also examines the psychological and behavioral aspects of digital distraction, digital dependency, and decreased self-regulation among students. Conclusion The current study also examines the psychological and behavioral aspects of digital distraction, digital dependency, and decreased self-regulation among students. In response, educators are considering strategies such as digital detox periods, device-free classrooms, and the use of educational technologies that encourage active learning rather than passive consumption. Funding Source n/a Topic Categories Immunology Education and Communication (EDU)

An antigen-less pro-vaccine to treat amyotrophic lateral sclerosis 2301013

Abstract Introduction Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that causes muscle paralysis and death within 2—5 years of diagnosis. Currently, there is no effective treatment. Emerging research suggests that regulatory T cells (Tregs) play a neuroprotective role in ALS; however, pathogenic antigens in ALS remain unknown, hindering the development of strategies to expand disease relevant Tregs. Recently, we developed an antigen less pro vaccines (ALPV) that can form an active vaccine in situ with endogenous pathogenic antigens overexpressed at disease sites. Here, we aim to explore this novel vaccine in an ALS mouse model. Methods To enable straightforward tracking and quantification of Tregs, a substrain of ALS prone mice was generated by crossing Foxp3 eGFP/Ki67 tagRFP mice with SOD1 G93A mice. Beginning at 12 weeks of age, mice were treated with ALPV; PBS injected mice served as controls. At defined time points post treatment, circulating Tregs were quantified via immunostaining and flow cytometry. Results Our results showed that ALPV treatment increased Treg levels approximately fivefold, with additional significant spinal cord data supporting this expansion. Next, behavioral studies will be conducted to determine whether ALPV can delay disease progression. Conclusion Our finding that ALPV significantly expands Tregs in treated mice highlights its promise as a novel treatment for ALS. Critically, by bypassing the need for an exogenous immunogen, ALPV may serve as a universal vaccine for other neuroinflammatory diseases, even in cases where pathogenic autoantigens remain unknown. Funding Source N/A Topic Categories Vaccines and Immunotherapy (VAC)

Signaling pathways via BAFF receptor/Nav1.7 channel contribute to the activation of monocytes and B cells in patients with Sjögren’s disease 2254637

Abstract Introduction We reported that the expression of a BAFF receptor, BR3, was enhanced in monocytes in patients with Sjögren’s disease (SjD), and that BAFF induced production of IL-6 by the cells. In addition, we found that IL-6 produced by BAFF-stimulated monocyte induced IgG production by co-cultured B cells. In our previous study, we also found that the inhibitors against Nav channel suppressed BAFF-induced IL-6 production by THP-1, a human monocytic leukemia cell line. Since the voltage gated sodium channel 1.7 (Nav1.7) was known to be involved in the production of IL-6 in monocytic lineage of patients of inflammatory diseases, we investigated the possible involvement of Nav1.7 in the BAFF signaling pathway in SjD monocytes. Methods The expression levels of BR3 and Nav1.7 in peripheral monocytes from patients with SjD (n = 108) and healthy controls (HC; n = 28) were analyzed by FACS. PBMCs were stimulated in vitro with a mixture of anti-IgM, anti-CD40, IL-21 and BAFF in the presence or absence of a specific inhibitor against Nav1.7. The amount of IgG produced by the cells was measured by ELISA. The expression level of Nav1.7 in the cells was analyzed by qPCR. Results The proportion of Nav1.7- and BR3-positive cells in monocytic population (Nav1.7+/CD14+, BR3+/CD14+) were significantly elevated in SjD as compared to HC. The Nav1.7+/CD14+ ratio was significantly correlated with BR3+/CD14+ ratio in SjD patients. Of note is that BAFF induced not only IL-6 production by SjD monocytes, but also the Nav1.7 expression in the cells. Moreover, a Nav1.7 specific inhibitor suppressed BAFF-induced IL-6 overproduction by SjD monocytes and elevated IgG production from stimulated PBMCs in a dose dependent manner. Conclusion These data and our previous data collectively suggest that Nav 1.7 signaling pathway is involved in the BAFF signaling pathway especially in IL-6 production by monocytes and IgG production by B cells in SjD. Funding Source n/a Topic Categories Cytokines and Chemokines and their Receptors (CCR)

A Non-Invasive Dissolvable Microneedle Platform for Liposome-Encapsulated rBmHAXT(ΔCys) Delivery Against Lymphatic Filariasis 2304452

Abstract Introduction Lymphatic filariasis is a mosquito-borne neglected tropical disease-causing lymphatic dysfunction and long-term disability. Despite global control efforts, no effective vaccine exists. Our laboratory developed Lf Guard, a cGMP-manufactured recombinant tetravalent rBmHAXT(ΔCys) antigen. Conventional injectable vaccines face challenges, including dependence on a cold chain, logistics, and needle-related barriers. These limitations highlight the need for a non-invasive delivery platform. We present a liposome-loaded dissolvable microneedle (Lipo-dMN) system designed to improve antigen stability, dermal targeting, and minimally invasive administration. Methods Cationic liposomes incorporating Lf Guard (1 mg/mL) were synthesized by thin-film hydration. Size, PDI, and zeta potential were measured by DLS; morphology by SEM. Encapsulation efficiency was quantified using BCA assay. Antigen integrity and functionality post encapsulation was assessed via SDS-PAGE and Western blot. Dissolvable microneedles were fabricated using PDMS molds containing 1000 µm-high pyramidal needles (200 µm base, 10 × 10 array) by centrifugation casting of HA—trehalose matrices with antigen-loaded liposomes, followed by a PVP backing layer. Needle structure was examined by SEM, and FITC-BSA liposomes were used only for tip-loading visualization. Results The optimized formulation showed a 264 nm size, 0.419 PDI, and +3.22 mV zeta potential, indicating stable vesicles. Encapsulation efficiency was high (≈98%). SEM confirmed spherical liposomes; SDS-PAGE and Western blot verified preserved antigen integrity. Microneedles showed uniform 1000 µm height and sharp, robust architecture. Fluorescence imaging confirmed accurate localization of liposomal cargo within needle tips. Conclusion The Lipo-dMN platform maintains antigen structure, achieves high loading efficiency, and provides precise intradermal deposition through a non-invasive, scalable vaccine delivery system for lymphatic filariasis. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)

Spatial Profiling Links Metabolic Reprogramming and Stromal Fibroblasts to PD-L1-Discordant NSCLC Responses 2309385

Abstract Introduction Understanding primary tumor features predicting post-recurrence immunotherapy response in resectable stage III non-small cell lung cancer (NSCLC) could guide adjuvant strategies. We hypothesized that spatial profiling of surgical specimens would reveal microenvironmental determinants of programmed death ligand-1 (PD-L1)-discordant responses to subsequent immunotherapy. Methods Surgical specimens from eight stage III NSCLC patients with post-recurrence progression were analyzed by Xenium 5K spatial transcriptomics. Patients were stratified into four PD-L1-high (≥50%) non-responders and four PD-L1-negative (< 50%) responders based on primary tumor PD-L1 expression and post-recurrence immune checkpoint inhibitor (ICI) response. Analyses included pathway enrichment, T cell exhaustion mapping, fibroblast subtyping, spatial neighborhoods, and NicheNet inference. Results Non-responders displayed elevated glycolysis and hypoxia pathways indicating metabolic reprogramming, while responders did not. Spatial analysis revealed T cell exhaustion proximal to tumors in non-responders with marked attenuation in responders. Fibroblast subtyping identified metabolically active CAFs (meCAFs) enriched adjacent to glycolytic tumors in non-responders, with tighter tumor-meCAF spatial coupling. NicheNet identified meCAF-derived VEGFA as a key signaling mediator targeting tumor cells, with predicted targets including ACKR3, PTGS2, and PLAU, implicating angiogenic-metabolic crosstalk driving immune exclusion. Conclusion Spatial profiling reveals that PD-L1-discordant ICI responses are determined by coordinated interactions of metabolically reprogrammed tumors, localized T cell exhaustion, and meCAF-driven signaling. These findings establish meCAF-VEGFA-tumor crosstalk as a therapeutic vulnerability and support spatially-resolved tumor-stroma profiling as a prognostic tool beyond PD-L1 for predicting ICI responses. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Decoding Gut microbial immunity: How Natural Killer T cells recognise Bacteroides fragilis glycosphingolipids 2256741

Abstract Introduction The human gut microbiota comprises more than 50% of Bacteroides species that produce small diffusible molecules like sphingolipids that play a key role in modulating the host’s immune responses. In particular, Bacteroides fragilis produces glycosphingolipids termed ‘BfaGCs’ that can activate type I Natural Killer T (NKT) cells. BfaGCs exhibit distinct structural characteristics, including truncated sphinganine chains, varied branching patterns, and specific functional groups, distinguishing them from the canonical type I NKT cell marker, α-galactosylceramide (KRN7000). Methods Using a combinatorial cellular immunology, mass spectrometry and X-ray crystallography approach, we provide the first insights into the molecular mechanism of recognition of four novel BfaGCs presented by the antigen-presenting molecule CD1d, in complex with the type I NKT TCR. Results The co-culture assay performed with bone marrow-derived dendritic cells and NKT cells in the presence of specific BfaGCs indicated that branching in their sphinganine chain is a critical determinant of NKT cell activation. The three-dimensional complex structures revealed that the TCR adopted a parallel docking topology atop the F’-pocket of CD1d in recognising the presented BfaGCs, reminiscent of other published type I NKT TCR lipid complexes. Nevertheless, the terminal sphinganine branching of BfaGCs facilitates unique interactions within the CD1d F’-pocket, thereby underpinning their distinctive agonistic properties. Also, the NKT TCR demonstrates high binding affinities for both stimulatory and non-stimulatory forms of CD1d-presented BfaGCs, affirming BfaGCs as bona fide CD1d ligands that modulate host immune defences via NKT cells. Conclusion Thus, BfaGCs were demonstrated to function as immunomodulatory mediators influencing the host’s defence in the context of NKT cells. Collectively, our findings enhance understanding of the symbiotic interplay between lipid-producing gut microbes and the host. Funding Source Australian Research Council Topic Categories Mucosal and Regional Immunology (MUC)

Phosphatidylserine on Hypoxic Tumor-Derived sEVs Regulates ADAM17 Activity and T-Cell Fate 2310261

Abstract Introduction Tumor hypoxia is a hallmark of head and neck squamous cell carcinoma (HNSCC) and promotes tumor prgression. Tumor-derived small extracellular vesicles (sEVs) are mediators of hypoxia-driven signaling and contribute to immune suppression within the tumor microenvironment. ADAM17, a membrane-associated sheddase regulating inflammatory and immune pathways, is sensitive to membrane lipid composition, particularly phosphatidylserine (PS). We investigated how hypoxia-induced lipidomic remodeling of tumor-derived sEVs affects ADAM17 activity and CD8+ T-cell apoptosis. Methods HNSCC cells (PCI-30) and normal keratinocytes (HaCaT) were cultured under normoxia (21% O₂) or hypoxia (1% O₂). sEVs were isolated by size-exclusion chromatography and characterized by nanoparticle tracking analysis, transmission electron microscopy, immunoblotting, and high-resolution untargeted lipidomics. Surface PS and ADAM17 expression were assessed by bead-based flow cytometry, and ADAM17 activity was measured using fluorogenic assays. Human CD8+ T cells were incubated with hypoxic or normoxic tumor-derived sEVs. PS-mediated interactions were blocked using Annexin V, and CD8+ T-cell apoptosis was quantified by flow cytometry. Results sEVs (125—135 nm) expressed Alix, CD63 and CD9 but not Grp94. Hypoxia selectively enriched PS species with mono-, polyunsaturated and very long acyl chains, reducing surface-exposed PS. Despite decreased PS exposure, hypoxic TEX displayed significantly increased ADAM17 expression and enzymatic activity, resulting in an elevated ADAM17/PS ratio. Functionally, hypoxic TEX induced higher levels of CD8+ T-cell apoptosis compared with normoxic TEX. Blockade of PS with annexin V significanlty reduced ADAM17 activity and attenuated TEX-induced CD8+ T-cell apoptosis. Conclusion Hypoxia alters phosphatidylserine organization in tumor-derived sEVs, enhancing ADAM17 activation, promoting PS-dependent CD8+ T-cell apoptosis, and facilitating immune evasion in HNSCC. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Novel autochthonous cancer model to investigate TCR signal strength in tumor-specific T cell differentiation 2334905

Abstract Introduction Immunotherapies demonstrate the potential power of CD8 T cells to eliminate cancer cells; however, these strategies only work in a subset of patients and tumor types. To design predictably effective immunotherapies, we must elucidate the mechanisms controlling tumor-specific T cell (TST) activation, dysfunction, and therapeutic response. T cell receptor (TCR) signal strength (determined by the affinity of TCR for peptide-bound major histocompatibility complex (pMHC)) is known to regulate T cell differentiation. However, its impact on anti-tumor immunity is less clear. Methods We developed a novel, inducible autochthonous cancer model in which we can systematically vary TCR signal strength, spanning the range observed for human tumor-infiltrating T cells: we cloned a Sleeping Beauty (SB) transposon/transposase-based vector encoding the oncogene MYC followed by an inverted inducible tumor model antigen (OVA). By single amino acid substitutions to the native OVA sequence, we generated altered peptide ligands that are recognized by OVA-specific CD8 T cells with varying TCR signal strength. SB-vectors, along with a vector silencing the tumor suppressor P53, were delivered via hydrodynamic tail vein injection into mice with inducible Cre expression, a highly-efficient method to induce liver tumors. Employing this model, we can track CD8 TST over months from tumor initiation to endpoints. Results We characterized CD8 TST in progressing tumors, and their response to immunotherapy. Tumors expressing high affinity epitopes induced TST expansion and TST ultimately acquired an exhausted phenotype with time. Tumors with low affinity epitopes lacked TST expansion. Strikingly, however, these TST could be activated through immunization, mediating robust anti-tumor immune responses. Conclusion We investigated how TCR signal strength determines T cell activation, differentiation, and anti-tumor activity, revealing interesting insights into how low-affinity TST can be therapeutically utilized in solid tumors. Funding Source NIH NCI R01CA269733 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

NiMo Dual‐Atom Dimers on Pd Nanosheets for Selective C─H and C─C Bond Cleavage of Ethylene Glycol From Waste Plastics (Adv. Mater. 46/2026)

Illuminating the Interface: In Situ Optical Insights Into Two‐Electron ORR Pathways for H ₂ O ₂ Electrosynthesis

ABSTRACT Hydrogen peroxide (H 2 O 2 ) is a prototypical green oxidant with wide applications. In pursuit of sustainable development, H 2 O 2 electrosynthesis via the two‐electron oxygen reduction reaction (2e − ORR) under mild, green, and decentralized conditions has emerged as a promising alternative to the industrial anthraquinone process. H 2 O 2 electrosynthesis is an interfacial electrochemical process in which appropriate surface active sites are critical for achieving high performance. To realize scalable H 2 O 2 production via 2e − ORR, in situ optical characterization is crucial for elucidating interfacial mechanisms and reaction principles, thereby facilitating further technological advances. This review is organized around the progressive enhancement of spatial resolution and accessible reaction information, and systematically summarizes in situ optical characterization methods for H 2 O 2 electrosynthesis via 2e − ORR, spanning one‐dimensional (1D) spectroscopy, two‐dimensional (2D) imaging, three‐dimensional (3D) reaction‐field imaging, and multimodal coupling that correlates optical, electrochemical, and structural information. It highlights the working principles, device configurations, and representative applications of these methods, and provides perspectives on future technological innovation and practical application of in situ optical characterization for advancing sustainable and economically viable H 2 O 2 electrosynthesis in support of green industry and carbon neutrality.

Prognostic signatures associated with immune and macrophage phenotypes in colorectal cancer: integrated single-cell and bulk transcriptomic analyses

Abstract Colorectal cancer (CRC) progression is closely associated with chronic inflammation and immune suppression mediated by M2 macrophages. This study systematically analyzed immune-related and macrophage polarization–related genes in CRC by integrating The Cancer Genome Atlas CRC dataset to identify differentially expressed genes. Prognostic genes were identified using regression and machine learning methods, followed by the construction of a risk model. Comprehensive analyses included gene set enrichment, immune microenvironment assessment, somatic mutation profiling, and drug sensitivity evaluation. Single-cell RNA sequencing identified key cell populations, whereas cell–cell communication and pseudotime trajectory analyses further characterized cellular dynamics. RT-qPCR validation preliminarily confirmed the findings. A three-gene signature comprising FABP4 , PPARGC1A , and LEP demonstrated strong prognostic value. Risk stratification based on this signature was associated with distinct immune cell profiles, pathway activities, mutational patterns, and drug sensitivity. Single-cell analysis identified macrophages as central interacting cells, with stable expression of the three genes during macrophage differentiation. Experimental validation further confirmed significant downregulation of these genes in CRC tissues. Overall, the FABP4 / PPARGC1A / LEP signature and its associated risk model demonstrate strong potential for predicting outcomes in patients with CRC.