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Recurrent pregnancy loss (RPL) is a complex disorder fundamentally linked to immune dysregulation at the maternal-fetal interface. While endometrial immune profiling provides critical diagnostic insights for managing RPL, its clinical application is limited by the invasive nature of endometrial biopsies. This study aimed to identify non-invasive, serum-based immunological and metabolic markers that accurately reflect local endometrial immune profiles, facilitating a less-invasive risk assessment and patient categorization. The study enrolled 106 participants, including 81 women with RPL and 25 fertile controls. The specimens of endometrium by doing biopsy of IL-15/Fn-14, IL-18/TWEAK, and CD56 expression were analyzed to categorize patients as having balanced, highly dysregulated (over-activated) and lowly dysregulated immune profiles. For each patient, blood samples from the same time frame were processed for immune profile (Th1/Th2 ratio), non-specific immune cell populations (NK), a metabolic profile containing autoantibody levels, and a metabolic screening of adiponectin, prostaglandin E2 (PGE-2), insulin-like growth factor-1 (IGF-1), and total phospholipids. All control subjects exhibited a balanced endometrial immune profile. In contrast, approximately 71% of RPL patients demonstrated immune dysregulation, with 46.9% showing an over-activated profile and 24.7% a low-activated profile. Systemically, the high immune dysregulation group exhibited significantly elevated peripheral NK cell frequencies and Th1/Th2 ratios compared to the balanced group. Furthermore, this over-activated group demonstrated a substantially higher prevalence of serum autoantibodies. Metabolically, high immune dysregulation was associated with significantly decreased serum adiponectin and IGF-1 levels, alongside markedly elevated PGE-2 and total phospholipid concentrations. These findings suggest that systemic metabolic and immune biomarkers may potentially reflect local endometrial immune status in women with RPL. Although these serum markers demonstrate promise as minimally invasive tools for immune profiling, further large-scale validation and predictive studies are required before they can be introduced as reliable alternatives to endometrial biopsy in clinical practice.

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Critical bone defects represent a global health challenge, necessitating specialized medical care and imposing significant costs on the public systems. In this context, many efforts in the tissue engineering and regenerative medicine framework have been made, focusing on developing biomaterials for bone regeneration. Additive manufacturing, known as 3D printing, has emerged as a promising technology for creating revolutionary biomedical devices. An advancement of this technique, 3D bioprinting, enables the fabrication of biomaterials intended for tissue regeneration and the transplantation of synthetic organs, using bioinks (cell-enriched hydrogels) and inks (hydrogels with or without bioactive agents) to produce a variety of devices, such as scaffolds, dressings, microneedles, and blood vessels. Thus, biopolymers have emerged as promising materials for the development of biomaterials and bioinks in tissue engineering because of their biocompatibility, biodegradability, low toxicity, and ability to mimic the extracellular matrix. Therefore, this review discusses recent advances in natural biopolymer-based bioinks for 3D bioprinting in bone regeneration, highlighting rheological properties, mechanical performance, biological functionality, and strategies such as chemical modification, nanomaterials, and smart systems. In addition, challenges related to vascularization, structural stability, immune responses, and clinical application are discussed.

Lipid-protein interactions are ubiquitous in biology, where they are fundamental to membrane structure, cell signaling, immunology, and metabolism. Despite the availability of thousands of experimentally determined lipid-protein structures, the molecular basis for lipid recognition and specificity across the lipid-protein interactome remains incompletely understood. Here, we report a systematic analysis of 113,782 annular and nonannular lipid-protein complexes spanning the eight lipid classes. Pairwise atomic interactions are linked to lipid and protein physicochemical properties and binding geometries. Hydrophobic contacts, hydrogen bonds, and salt bridges contributed to over 99% of lipid-protein interactions. Lipid class-, protein sublocalization-, protein function-, and protein fold-dependent trends were identified. Protein pockets were finely tuned for lipid size, shape, and polarity: fatty acyls associated with narrow, moderately hydrophobic pockets; saccharolipids and glycerophospholipids bound to larger, polar cavities; and sterols and prenols preferentially occupied compact hydrophobic sites. Global analysis across different protein families identified similarities in interaction profiles, while also highlighting protein-specific recognition adapted to biochemical function. Lipid-protein interaction maps were projected onto lipid structures to uncover conserved and divergent hotspots and coldspots across lipid classes. The heatmaps imply that recognition and specificity are mediated by tailored anchoring of polar head groups and varying interaction with hydrophobic tails. Together, the data establish nature's principles governing lipid binding, lipid selectivity, and complex stability, and collectively provide a molecular atlas of the lipid-protein interactome. The work enables the elucidation of lipid biology at scale and establishes guiding principles for the rational design of chemical probes and therapeutics targeting lipid biology.

Post-COVID condition (PCC) encompasses a spectrum of clinical symptoms affecting multiple organs that persist for >3 months after resolution of the initial SARS-CoV-2 infection. The complex nature of PCC symptoms makes it difficult to decipher the mechanistic basis of disease and establish efficient pharmacological interventions. However, non-pharmacological approaches such as personalized physical exercise regimen has been shown to improve the quality of life in PCC patients. Among the non-pharmacological interventions for PCC, physical rehabilitation, especially symptom-titrated physical exercise, has shown promise in restoring the quality of life but the underlying mechanisms are not yet elucidated. This personalized approach adjusts the physical training intensity according to patient's ability and tolerance levels. We had observed that individuals with PCC showed significant improvement following tailored physical exercise. Here the plasma samples obtained before and after the intervention was analyzed for a preselected panel of 1500 markers by SomaScan assay. Proteins differentially expressed between the exercise and no-exercise groups suggest that the tailored exercise training drives distinct proteomic signatures involved in immune, vascular and oxidative stress pathways. Despite the low sample numbers, our results indicate that the tailored exercise regimen resulted in significant alterations in biological pathways associated with PCC.

Active semiflexible filament collectives, ranging from motor-driven cytoskeletal filaments to slender organisms such as cyanobacteria and worm aggregates, abound in nature. Yet how activity and flexibility jointly govern their organization, especially isotropic-nematic (I-N) transition, remains poorly understood. Performing large-scale Brownian dynamics simulations of 3D active semiflexible polymers with varying flexibility degrees, we show that tangential active forces systematically shift the I-N transition to higher densities, with the shift controlled by the flexibility degree and activity strength. Strikingly, activity alters the nature of the transition: discontinuous at low strengths, continuous at moderate strengths, and ultimately suppressed at high activity levels. The delayed I-N transition originates from enhanced collective bending fluctuations, resulting in chain shrinkage and enlargement of effective confinement tube. At moderate activity levels, these fluctuations can trigger large-scale excitations that stochastically drive temporal transitions between nematic and isotropic states, indicating an activity-induced instability of the nematic field. We summarize this behavior in nonequilibrium state diagrams of density and activity for different flexibility degrees.

Mouse models remain the premier preclinical model organisms for cancer immunotherapy, yet how they faithfully recapitulate the human tumor microenvironment (TME) has remained poorly defined. In a recent Nature Immunology study, Courau and colleagues addressed this gap through a systematic, cross-species immune profiling spanning 15 widely used mouse models and corresponding human cohorts. Their analysis revealed that commonly used mouse tumors only capture a portion of human disease-predominantly macrophage-rich, T-cell-poor microenvironments, but largely miss immune-rich, CXCL13-organized human tumor types, which are more responsive to immune checkpoint blockade in clinic. Beyond cellular composition, the authors also uncovered species-specific chemokine networks and cell-cell interactions that may account for the unique immune profiles in mouse and human. Despite the differences, conserved transcriptional modules were detected by consensus gene expression profile (GEP) analysis. Notably, a strong association between interferon-responsive myeloid cells and T-cell cytotoxicity marks a key transcriptional program where mouse and human biology converge, which is able to predict patient survival. Taken together, this work serves as a cautionary guide to the limitations of mouse models; more importantly, it offers a queryable atlas for precisely aligning preclinical models with the human conditions they credibly emulate.

Immune checkpoint inhibitors (ICIs) have transformed oncology practice. However, treatment response remains heterogeneous, rendering predictive biomarkers critical for optimal patient care. The 3 established biomarkers, programmed death-ligand 1, tumor mutational burden (TMB), and microsatellite instability-high/deficient mismatch repair, are approved and clinically validated but are modest predictors of benefit. As a result, multiple novel predictive biomarkers remain under investigation. This review highlights established and investigational predictive ICI efficacy biomarkers. For established biomarkers, we describe biology, assay modalities, approved companion diagnostics, landmark studies, and notable limitations. Due to the multisystem nature of antitumor immune effects, investigational biomarkers span multiple domains, including tumor genomic biomarkers (e.g., mutational signatures, TMB, neoantigen clonality), tumor microenvironment (e.g., tumor-infiltrating lymphocytes [TILs], tertiary lymphoid structures), systemic immune biomarkers (e.g., cytokines, autoantibodies, glycoproteins, peripheral blood mononuclear cells), and the microbiome (e.g., gastrointestinal microbial diversity, responder-enriched taxa). The established biomarkers PD-L1, TMB, and microsatellite instability-high/deficient mismatch repair inform ICI use in clinical practice but have important limitations. Multiple investigational biomarkers show promise in refining patient selection and optimizing therapy. Moving forward, increased assay harmonization, prospective validation, and standardized parameters may improve performance. Composite models integrating complementary signals across domains may further individualize treatment and lead to an era of personalized cancer immunotherapy.

Atopic dermatitis (AD) and rosacea have traditionally been regarded as two distinct inflammatory skin disorders with divergent pathophysiology. However, emerging evidence has progressively revealed unexpected convergences between these conditions in clinical manifestations, comorbidity profiles and pathogenic mechanisms-raising the question of whether the apparent mechanistic overlaps represent true pathophysiological convergence-sharing common upstream drivers-or merely parallel, non- specific innate immune responses triggered by entirely distinct microbial and genetic factors? This distinction carries profound implications for the design of shared versus disease-specific therapeutic strategies. this review aims not simply to enumerate similarities but to critically evaluate whether the observed convergences represent true mechanistic overlap, or parallel but independent responses. Literature search strategy: A comprehensive literature search was conducted in PubMed, Embase and Scopus, the Cochrane Library between April, 2016 and April, 2026. The search strategy combined controlled vocabulary and free-text terms, including " rosacea", " atopic dermatitis", " mast cells", " comorbidity", " microbiome", " innate immunity", " adaptive immunity", and " neurovascular". Reference lists of relevant articles were also manually screened to identify additional eligible studies. Studies were included if they: (1) focused on atopic dermatitis and/or rosacea; (2) investigated relevant immunological mechanisms, comorbidities, or pathophysiological pathways; and (3) provided sufficient data to support qualitative synthesis. Both original research articles and high- quality reviews or meta-analyses were considered. Studies were excluded if they: (1) were duplicate publications; (2) lacked sufficient methodological detail or extractable data; or (3) were not directly relevant to the objectives of this review. Study selection and data extraction were performed independently by two reviewers. Titles and abstracts were initially screened, followed by full-text assessment for eligibility. Any discrepancies were resolved through discussion, and when necessary, a third reviewer was consulted to reach consensus. A total of 5381records were identified through database searching, with an additional 83 records identified through manual reference screening. After removal of duplicates, 3185records remained for title and abstract screening, of which 2864 were excluded due to irrelevance. A total of 321 full-text articles were assessed for eligibility, and 216 were further excluded for the following reasons: lack of relevance (n =117), insufficient data (n =53), or low methodological quality/non-original articles (n = 46). Ultimately, 105 studies were included in the qualitative synthesis. The study selection process is summarized in a PRISMA-style flow diagram (Graphical Abstract, below). Given the narrative nature of this review, no formal risk-of-bias assessment was performed. Critical appraisal of the evidence reveals that both diseases share an upstream innate immune activation platform' encompassing TLR2/TLR4 signaling, NLRP3 inflammasome activation, mast cell degranulation and neurovascular dysregulation via the CGRP/SP/VEGF/TRP axis. However, they diverge at the level of adaptive immune polarization: AD is dominated by Th2/ILC2 skewing with IgE sensitization and deficient antimicrobial peptide responses, while rosacea is characterized by Th 1/Th17 involvement with autonomous LL-37 overproduction as its primary amplification loop. Intriguingly, dupilumab-induced rosacea-like dermatitis suggests that these polarization states may not merely differ but actively compete, raising questions about the nature and limits of mechanistic overlap between the two conditions. This duality may challenge simplistic models of mechanistic overlap and has direct implications for differential clinical management. Future research should employ multi-omics approaches and prospective comorbidity cohorts to clarify causal pathways and translate mechanistic insights into optimized therapeutic strategies.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of end-stage kidney disease, yet disease-specific therapeutic options remain limited. Emerging evidence implicates gut microbiota dysbiosis and innate immune activation, particularly NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome-related signaling, in IgAN pathogenesis. However, whether human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) are associated with changes in renal injury and gut-immune-related parameters in IgAN remains unclear. hUCMSC-Exos were isolated and administered to an IgAN-like mouse model. Renal function, histopathological changes, and systemic inflammatory markers were assessed. Gut microbiota composition was analyzed using 16S rRNA sequencing, and exploratory microbial co-occurrence networks were constructed. In vitro, podocytes stimulated with galactose-deficient IgA1 (Gd-IgA1) were used to evaluate inflammasome-related markers following exosome exposure. Transcriptomic data from human IgAN glomeruli (GSE93798) were analyzed to explore inflammatory and immune-related gene signatures. hUCMSC-Exos were associated with changes in renal injury markers in IgAN-like mice, along with alterations in gut microbial composition. Microbiome analysis showed a shift toward a microbial profile closer to controls, with enrichment of bacterial taxa previously reported in association with gut metabolic homeostasis in other cohorts, including Anaerostipes, Dorea, and Ruminococcus. These taxa showed correlations with renal dysfunction indicators and inflammatory markers and were identified as hub taxa in an exploratory co-occurrence network. Transcriptomic analysis of human IgAN glomeruli revealed altered expression of NLRP3 inflammasome-related genes and aryl hydrocarbon receptor (AhR)-related signaling components, suggesting context-dependent inflammatory activity requiring further validation. In vitro, hUCMSC-Exos were associated with reduced levels of NLRP3, IL-1β, and IL-18 in Gd-IgA1-stimulated podocytes. hUCMSC-Exos were associated with changes in renal injury markers in an IgAN-like model, accompanied by alterations in gut microbiota composition and inflammasome-related inflammatory markers. These findings are consistent with a potential association between gut microbiota, innate immune-related signaling, and renal injury in IgAN. hUCMSC-Exos may represent a cell-free candidate for further investigation in IgAN. However, these observations are descriptive and associative in nature, and causal mechanisms cannot be inferred from the present study.

CAR-T cell therapy has shown great success in hematological malignancies. However, this immunotherapeutic strategy faces critical challenges in solid tumors mainly due to the key hurdles brought about by the hostile tumor microenvironment (TME). Effective CAR-T cell therapy in solid tumors is hampered by low tumor infiltration of the administered T cells due to the dense fibrotic nature of the TME and its aberrant vasculature. Also, solid tumors shape a highly immunosuppressive milieu in which the cytotoxic activity and persistence of functional CAR-T cells are abolished. Trefoil factor family (TFF) peptides, especially TFF3, have recently drawn a lot of attention due to their pro-tumor activities. Based on the recent evidence, TFF3 is upregulated in solid tumors where it plays roles in chemotherapy resistance, increased survival, and proliferation of cancer cells, expansion of the immunosuppressive cells and enhanced angiogenesis, which contributes to the aberrant tumor vasculature. In this review, we explore how TFF3 signaling contributes to tumor progression and immune escape, and how its inhibition might reshape the tumor microenvironment (TME) to better support CAR-T cell activity. Mounting evidence suggests that blocking TFF3 could help reduce immunosuppression, restore more normal blood vessel structure, and disrupt the pro-fibrotic and tumor-promoting interactions driven by cancer stem cells (CSCs). At the same time, since TFF3 plays an important role in protecting mucosal tissues and promoting repair after injury, its inhibition needs to be approached carefully. We also discuss strategies to selectively block TFF3 within tumors while minimizing unwanted effects on healthy tissues. Gaining a deeper understanding of how TFF3 contributes to therapy resistance may open up new opportunities to enhance CAR-T cell treatment in solid tumors, either through combination therapies or as a preconditioning step before CAR-T cell infusion.

Every year, approximately 13 million infants are born preterm (<37 weeks gestation). Preterm-born infants experience disproportionately high infection-related morbidity and mortality, reflecting the immaturity of their immune system, especially early in life. This review provides an up-to-date overview of the phenotype and function of the immune system in preterm infants compared with term infants, with an emphasis on adaptive immunity. At birth, both innate and adaptive immune cells of preterm infants show phenotypic and functional immaturity. In addition, antibody levels are reduced, and immunogenicity of some vaccine components is diminished, contributing to impaired pathogen clearance and suboptimal vaccine responses. During the first year of life, rapid maturation occurs and differences with term infants become less pronounced or disappear. This review provides readers with a framework for understanding the immunologic mechanisms underlying the increased infection risk in preterm-born infants. Recognizing the all-encompassing nature of immune immaturity in preterm infants is essential for the development of integrated strategies to further improve health outcomes.

There is a constant tug-of-war for transition metals at the pathogen-host interface. Vertebrate hosts modulate the availability of metals to pathogens in a process known as nutritional immunity, but pathogens have evolved numerous countermeasures to this host defense strategy. The bioavailability of trace metals therefore shapes the outcome of disease. In mammals, epithelial cells lining the intestine are a major site of metal absorption. Intestinal epithelial cells (IECs) are also a target for invading enteric pathogens but the contribution of epithelium-intrinsic factors toward nutritional immunity is unclear. Using Salmonella enterica serovar Typhimurium (STm) harboring genetically encoded fluorescent sensors for transition metals, we mapped the spatiotemporal nature of metal competition during enteric salmonellosis. In contrast to the metal replete lumen, a subpopulation of STm experience a temporal, cell-specific restriction of Fe2+ and Zn2+ (&#x2264;0.1 &#xb5;M), and possibly Mn2+, in both IECs and cells of the lamina propria during the early stages of infection. We further studied the contribution of the broad specificity divalent metal transporter, SLC11A2, in IECs to nutritional immunity against STm. SLC11A2 was recruited to maturing Salmonella-containing vacuoles and knockout of SLC11A2 led to increased bacterial proliferation in IECs. Metal-responsive fluorescent reporters showed that vacuolar STm were less starved for Fe2+, and possibly Mn2+, but not Zn2+ or Mg2+ in the absence of SLC11A2. STm counters SLC11A2-mediated growth restriction in IECs via the Mn2+/Fe2+ transporter, MntH, and iron-binding siderophores. We conclude that SLC11A2-mediated sequestration of a subset of metals is an IEC innate defense mechanism against STm.

Over the last decade, immune checkpoint inhibitors (ICIs) have become a cornerstone of the treatment of multiple cancer types. Several factors influence ICI efficacy and toxicity, and current research is investigating whether circadian timing of administration is one of them. This review is limited in scope to ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-LAG-3) and does not detail other immunotherapeutic modalities (oncolytic viruses, cytokine therapies, adoptive cell transfer, cancer vaccines). We synthesised the findings, which are consistent with a role for the circadian rhythm in modulating normal immune function, including reported circadian variation in the activity of specific checkpoint molecules and immune cell populations. Several studies, predominantly retrospective, have reported associations between earlier-in-the-day ICI infusion and more favourable efficacy outcomes; however, the evidence base is heterogeneous, and the first randomised phase III trial currently subject to a Nature Medicine Editor's Note suggests that time of day (ToD) of ICI administration may be associated with differences in efficacy, with more heterogeneous signals for toxicity. Given the risk of immortal-time bias, cycle-number confounding and scheduling bias in retrospective datasets, additional multicentre prospective randomised trials are required to establish causality and reproducibility, alongside research into circadian biomarkers that could help personalise timing in routine clinical care.

Foot-and-Mouth Disease (FMD) is a highly contagious viral infection affecting cloven-hoofed animals and remains a major threat to livestock productivity in India. The present study was undertaken to assess the serological status of FMD virus infection among bovines and goats in the Union Territory of Puducherry, India, with emphasis on the potential role of goats as sentinel species in FMD surveillance. A total of 1,608 serum samples, comprising 828 from goats and 780 from bovines were collected from the four enclaves of Puducherry, namely Puducherry, Karaikal, Mahe, and Yanam. The samples were tested using ICAR-NIFMD r3AB3 NSP iELISA to detect antibodies against the 3AB non-structural protein of FMDV. The overall NSP antibody seropositivity was 5.43% (45/828) in goats and 11.15% (87/780) in bovines, suggesting low level virus circulation of subclinical nature in the absence of reported outbreaks. Among districts, Yanam reported the highest positivity rate of 16.1% (5/31), followed by Puducherry with 6.93% (38/548), Karaikal with 0.95% (2/210) while no positive samples were detected in Mahe 0.0% (0/39), whereas in bovines (cattle and buffalo), Puducherry reported the highest positivity rate of 13.58% (72/150), followed by Karaikal with 8.62% (15/174). No positive samples were detected in Mahe 0.0% (0/30) and Yanam 0.0% (0/46). The results highlight localized clustering of infection and heterogeneity in exposure within and between enclaves and species. NSP antibody detection in goats from regions without reported outbreaks reflects silent viral exposure, providing field-level evidence of virus circulation. This finding demonstrates the potential usefulness of goats as sentinel animals for FMD surveillance in endemic settings for freedom from virus circulation. The study underscores the need for incorporating small ruminants into routine FMD surveillance and strengthening multispecies monitoring to support India's long-term FMD control and eradication goals.

Chronic bacterial respiratory infections by Staphylococcus aureus are a hallmark of cystic fibrosis (CF) lung disease, affecting up to 80% of all people with CF by their mid-teens. S. aureus is able to survive and persist in the CF lung despite robust neutrophilic inflammation. As neutrophils are the immune system's front line of defense against bacteria, the persistent nature of S. aureus infections in CF indicates both a defect in the ability of neutrophils to kill S. aureus and an enhanced ability of the bacteria to survive. S. aureus persistence in the CF lung is driven by both microbial and host, genetic and microenvironmental, factors. There doesn't seem to be one unifying feature that makes S. aureus more virulent in the CF lung as several factors have been proposed to aide its survival. These include increased resistance to antibiotics, the ability to form small colony variants, biofilm formation, co-infection with Pseudomonas aeruginosa, and several virulence factors such as the accessory gene regulatory system, leukocidins, and staphylococcal protein A. A variety of host factors also affect the ability of neutrophils to kill S. aureus in the CF lung. Defects in the function of the cystic fibrosis transmembrane conductance regulator, the genetic cause of CF, affect phagolysosomal killing and lead to increased formation of neutrophil extracellular traps, which are less effective at killing S. aureus. Additionally, data suggest that factors within the CF lung microenvironment also affect neutrophilic killing of S. aureus. However, more research is needed to clearly identify what these environmental factors may be. This review article summarizes the current knowledge on the clinical relevance of S. aureus lung infections in CF, on microbial and host mechanisms promoting S. aureus survival in the CF lung, and on details of neutrophil-S. aureus interactions in CF. By understanding how S. aureus is able to survive in the CF lung and why neutrophils are unable to kill this bacterium, it could be possible to identify potential therapeutic targets to alleviate the consequences of S. aureus respiratory infection in CF.

Glioblastoma remains one of the most lethal solid tumours, with recurrence driven by highly migratory residual cells that escape resection and resist adjuvant radiochemotherapy and arise from underlying genetic heterogeneity that promotes both a migratory phenotype and therapy resistance. These invasive populations exploit endogenous chemotactic cues, including hypoxia induced signalling, postoperative wound-healing cytokines, perivascular niche factors, and interstitial or cerebrospinal-fluid-driven transport, to disperse through the brain and re-establish tumour mass. While efforts to therapeutically inhibit chemokine pathways have been extensive, clinical trials targeting CXCR4, CCR2, CCR5, and CXCR1/2 have demonstrated limited survival benefit, in part due to ligand-receptor redundancy, network compensation, and the inherently spatial nature of chemotactic signalling. Emerging strategies instead seek to exploit chemotaxis by engineering chemoattractant gradients capable of directing glioblastoma cells toward a defined location, such as an implantable scaffold or hydrogel placed in the resection cavity. This review synthesises the biological principles underlying chemokine- driven migration, the spatial organisation of tumour- associated gradients, and the engineering considerations required to generate stable, localised chemotactic fields. We give an overview of biomaterial platforms designed for chemokine delivery and summarise the preclinical evidence supporting tumour cell trapping or redirection in vivo. Finally, we outline the major biological, engineering, and regulatory barriers to translation, including gradient stability, unintended immune recruitment, fluid-flow-driven distortion, chemokine instability, and sterilisation challenges. Together, these insights establish a conceptual and practical framework for using engineered chemotactic guidance as a therapeutic strategy and highlight opportunities for next-generation "migration-sink" devices to improve local control of glioblastoma.

Tumor-associated antigens (TAAs) are non-mutated antigenic peptides expressed in cancer tissue at abnormally high levels but in normal tissue either at negligible levels, during only particular developmental stages, or in a tissue-restricted manner. The shared nature of TAAs across patients makes them attractive targets for off-the-shelf immunotherapies. However, no studies have comprehensively surveyed the TAA potential of all possible wild-type peptides originating from cancer-associated genes. In this study of 16 cancer tissue types and 39 normal tissue types, we analyzed the expression profiles of protein-coding genes to identify those with aberrantly high RNA levels across multiple solid tumor types and low RNA levels across all normal tissue types examined. We then developed a score to quantify tumor specificity of gene expression. Compared to previously reported TAA genes, those we identified exhibited substantially greater tumor specificity. Seven of these genes demonstrated consistently elevated expression in at least five tumor types and minimal expression across all non-immune-privileged normal tissues. To assess Human Leukocyte Antigen (HLA) class I presentation potential of the multi-cancer-associated genes, we computationally predicted the binding affinities between the most common class I HLA alleles and all possible wild-type TAA epitopes of 8-11 amino acids arising from those genes. We then applied rigorous filtering criteria to prioritize the most promising multi-cancer TAA peptide candidates and evaluated their HLA binding and cell-surface presentation using T2 and immunopeptidome analysis. Our results highlight new potential targets for multi-cancer immunotherapies.

Dendritic cells (DC) play a central role in host immunity as they carry environmental cues from sites of infection to the lymphatics, where they subsequently direct appropriate adaptive immune responses. Importantly, this process is exploited by pathogens such as HIV-1, which utilize DC to efficiently facilitate HIV-1 trans-infection of CD4+ T cells. In this study, we show that monocyte-derived DC matured under type-1 proinflammatory conditions, either through exposure to soluble mediators of type-1 immunity or through bystander activation of cytotoxic T cells, display enhanced trans-infection capacity, while prostaglandin E2 exposure diminishes this trait. This heightened trans-infection activity involves DC upregulation of sialic acid binding immunoglobulin-like lectin-1 (Siglec-1/CD169) surface expression and a distinct responsiveness to the CD4+ T helper cell signal CD40L. The upregulated expression of Siglec-1 increases HIV-1 surface binding potential on these proinflammatory DC, while CD40L/CD40 signaling uniquely induces the formation of pronounced morphologic extensions and the release of the chemokine CCL20, together increasing CD4+ T cell access and susceptibility to HIV-1 infection. Overall, this study demonstrates that the nature of environmental signals received by monocyte-derived DC during maturation and the character of their subsequent responsiveness to CD40L-expressing T helper cells dictates their ability to facilitate HIV-1 trans-infection.