Type 1 diabetes (T1D) has long been viewed as an immune-driven disease characterized by the destruction of otherwise healthy pancreatic beta cells. However, growing evidence indicates that beta cells may actively contribute to disease initiation. Intrinsic dysfunction - such as impaired protein processing, endoplasmic reticulum stress, neoantigen formation, and early upregulation of major histocompatibility complex (MHC) class I - could increase beta-cell immunogenicity and promote autoimmune recognition. This emerging paradigm has significant implications for prevention and therapeutic strategies.

Dendritic cell (DC) vaccines offer professional antigen presentation but are often limited by suboptimal trafficking to lymphoid tissues, whereas whole tumor cell vaccines preserve antigenic diversity yet frequently lack coordinated activation cues for efficient T cell priming. Here, we report OncoAPC, an inactivated artificial antigen-presenting cell designed around a triple-signal priming logic: MHC-I-mediated antigen presentation (signal 1), CD80-mediated costimulation (signal 2) with checkpoint-insulating capacity, and incorporated IL-12 (signal 3). Mechanistically, OncoAPC directly activated T cells while partially insulating against PD-1 suppression through cis CD80:PD-L1 interactions and simultaneously engaged endogenous DCs to relay tumor antigens via cross-dressing and amplify lymphoid priming. Across multiple tumor models, OncoAPC showed broad therapeutic activity, including marked suppression of metastatic tumor burden and substantial control of established tumors, outperforming conventional DC vaccination. It further retained efficacy beyond the MC38 backbone and remained active when generated from human tumor cells or excised tumor-derived material. These findings establish OncoAPC as a scalable, broad-spectrum cancer vaccine platform that integrates antigenic diversity with DC-like functional precision.

Extracellular vesicles are shifting the paradigm in vaccine development by virtue of their diverse benefits as carriers of immunogens to targeted hosts. These nano-sized naturally occurring biomolecules offer safety, transmissibility across membranes, excellent presentation of antigens and robust immune responses when engineered as vaccine delivery vehicles. Given the remarkable potential of these nanoscale biological carriers, the scientific community has witnessed substantial escalation in research activity highlighting their applications in vaccines and drug delivery. However, the research is still in its early stage and the scientists are actively striving to optimize the engineering of these molecules for effective therapeutic applications. As a research group working on similar lines, we sought to explore the diverse engineering strategies with the aim of understanding the potential of extracellular vesicles as potent vaccine delivery vehicles. We conducted a systematic search to critically screen original research studies investigating engineering of extracellular vesicles for production of vaccines against viral infections. Our analysis of the studies revealed that extracellular vesicles provide diverse engineering opportunities to enable efficient viral antigen presentation, and to elicit robust immune responses both in vitro and in vivo. A wide spectrum of viruses has been targeted driving development of versatile as well as pathogen-specific vaccine strategies. Advancing research in this domain could deepen mechanistic insight into viral infections, while opening novel pathways for translational application, drug delivery and vaccine design. We conclude that substantial opportunities remain to fully harness the potential of extracellular vesicles in biomedical research, particularly in context of viral infections.

Respiratory syncytial virus (RSV) infection often elicits ineffective long-term immune responses due to inefficient immune priming, complicating disease management and vaccine development. Dendritic cells (DCs) are central regulators of antiviral immunity and antigen presentation; yet, the direct impact of RSV on these pathways remains poorly understood. In this study, we identify sustained HLA-DM expression as a unique hallmark of RSV infected CD1c+ DCs, a phenotype not observed following influenza infection or poly(I:C) stimulation. Using single cell RNA sequencing, pharmacological inhibition, and complementary controls, we demonstrate that TBK1 dependent Type I Interferon signaling is a key regulator of HLA-DM expression during DC maturation. Co-culture experiments further suggest that HLA-DM-high DCs influence CD4+ T cell differentiation, supporting a model in which sustained HLA-DM expression reshapes antigen presentation and downstream adaptive immunity. Together, these findings uncover a previously unknown link between innate antiviral signaling and antigen presentation machinery in human DCs.

The Human Cytomegalovirus (HCMV) gH/gL/UL128/UL130/UL131A complex (Pentamer) is among the candidates for the development of a vaccine against HCMV; indeed, it brought to more immunogenic formulations which were able to protect the fetus against vertical transmission in pregnant women. Pentamer-specific antibodies have shown to be hundredfold more potent than gB or gH/gL antibodies, endowed with strong neutralizing activity. The often inadequate antibody immune response elicited by glycoprotein antigen has been, in part, attributed to the abundance of glycosylation on the protein. Here, we determine the composite glycan population of each of the N-linked and O-linked glycosylation sites present on the Pentamer by multienzymatic proteolysis and mass spectrometry; furthermore, total N-glycans profiles of Pentamer expressed in different cell systems have been compared exploiting the glycan fluorescent labeling and the immunogenicity of Pentamer with different glycosylation patterns has been investigated. Our analysis reveals the presence of underprocessed oligomannose-type glycans on some glycosylation sequons, which are probably derived as a result of sterically reduced accessibility to glycan processing enzymes. Furthermore, the antigen glycosylation pattern affects the elicitation of neutralizing antibodies in mice.

Platelets correspond to one of the most abundant components of the blood and shape the tumor microenvironment, modulate antitumor immune responses, and influence clinical outcomes in cancer patients. Recent studies have expanded our understanding of the mechanisms underlying platelet-immune interactions in cancer, including antigen presentation, immune cell activation, and immunosuppressive signaling. Consequently, platelet-based and platelet-targeted therapies have emerged as promising strategies for enhancing antitumor immunity and improving responses to immunotherapy. However, specifically targeting tumor-educated platelets while minimizing adverse effects, particularly bleeding complications, remains a major challenge. In this review, we summarize the current evidence supporting the dual role of platelets in cancer immunity and discuss how engineered platelets may be leveraged to optimize therapeutic outcomes, highlighting their potential clinical applications and the integration of platelet-targeted approaches into next-generation cancer immunotherapies.

This study examines sulfamethoxazole (SMX), a sulfonamide antibiotic strongly associated with severe cutaneous adverse effects, as a potential regulator of invariant natural killer T (iNKT) cells. This work combines molecular docking (to evaluate the likelihood of SMX binding to residues within a conventional binding pocket), molecular dynamics (to assess the stability of SMX binding and the forces that may destabilize the interaction), flow cytometry (to evaluate iNKT-cell activation in the presence of SMX within the context of established antigen presentation models), and particularly Raman spectroscopy (to investigate whether SMX-associated spectral features are retained after co-incubation and interaction) directly on sorted iNKT cells. Functional activation was assessed through IFN-γ production from sorted iNKT cells and correlated with Raman spectral data to support our hypothesis. The Raman spectroscopy was performed on both CD1d dimer (in isolation) as the presenter molecule of the drug and in sorted iNKT cells (in isolation), to identify spectroscopic evidence of drug-CD1dimer or drug-cell interactions under near-physiological conditions. From the CD1d experiment, we observed spectral features consistent with potential interactions between CD1d and serum-derived lipids, in a manner comparable to the positive control (α-GalCer). From the iNKT experiment, peaks at 1610 and 1663 cm-1 are the representative peaks that emerge under SMX stimulation conditions in iNKT cells (through TCR binding), as identified by second principal component (PC2) analysis. From the complete experiment, (CD1d + iNKT) suggests the possibility of a direct interaction between SMX and iNKT TCRs. Flow cytometry analysis further demonstrated a significant increase in ZAP-70 phosphorylation in sorted iNKT cells exposed to SMX under serum-free conditions, supporting the possibility of proximal TCR-associated signaling in the absence of CD1d.

Recombinant herpesvirus vectors have emerged as highly potent platforms for next-generation vaccine development, distinguished by their genomic capacity and their unique ability to elicit durable, long-lasting immunity through persistent latent infections. In this review, we trace the evolutionary trajectory of herpesvirus vector engineering-transitioning from traditional homologous recombination to advanced bacterial artificial chromosome (BAC) systems and precise, scarless CRISPR/Cas9 gene editing. We comprehensively evaluate the rational design of classical animal herpesvirus vectors, including pseudorabies virus (PRV), herpesvirus of turkeys (HVT), and feline herpesvirus type 1 (FHV-1). Specifically, we highlight their distinct advantages in molecular attenuation, the optimization of non-essential insertion loci, and the application of tissue-specific promoters for multiplexed antigen presentation. Furthermore, we discuss the strategic deployment of multivalent herpesvirus vaccines within the "One Health" framework, emphasizing their critical role in simplifying immunization protocols and interrupting the transmission chains of zoonotic diseases. Finally, we address the prevailing translational bottlenecks, including scalable manufacturing challenges and stringent regulatory frameworks regarding environmental release, providing perspectives on how continuous biotechnological innovations will empower herpesvirus vectors to serve as formidable prophylactic tools against emerging and re-emerging infectious diseases.

[This corrects the article DOI: 10.3389/fimmu.2026.1783909.].

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, increasingly implicated in the pathogenesis of several autoimmune diseases, such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). These diseases have both, shared and disease-specific immunopathogenic pathways involving EBV. Shared mechanisms include the role of EBV latent proteins in triggering immune dysfunction, molecular mimicry between viral and self-antigens, infection of autoreactive B-cells, and dysfunction of type 1 interferon (IFN-1) responses. In MS, EBV is associated with a CNS-compartmentalized CD8[+] T-cell responses, molecular mimicry with neural antigens, and formation of meningeal tertiary lymphoid structures. In SLE, EBV contributes to systemic autoimmunity through mimicry with multiple autoantigens, recurrent viral reactivation, and IFN-driven multi-organ inflammation. In RA, EBV promotes the formation of synovial ectopic lymphoid structures, enhances anti-citrullinated protein antibody production, and drives proinflammatory cytokine dysregulation. Host genetic variations, particularly in HLA alleles, further modulate susceptibility by influencing antigen presentation, viral control and autoreactive T-cell responses. Rather than acting as a uniform and consistent trigger, EBV appears to function as a context-dependent immunological modifier whose pathogenic effects are influenced by factors such as the timing of infection, tissue microenvironment, HLA-associated genetic background, and other environmental exposures. Unravelling the details of these mechanisms may inform targeted preventive and therapeutic strategies for EBV-associated autoimmune diseases.

The tumor microenvironment (TME) is increasingly recognized as a temporally organized ecosystem rather than a static structural niche. Circadian rhythms, generated by transcriptional-translational feedback loops involving CLOCK, BMAL1, PER, CRY, REV-ERB, and ROR, coordinate systemic physiology and local cellular programs that are directly relevant to tumor initiation, progression, and therapeutic response. In this review, we summarized how circadian regulation shapes tumor rhythmicity across multiple biological scales, from central clock-mediated synchronization to peripheral clocks within epithelial cells, stromal cells, adipocytes, and immune populations. Emphasis is placed on the spatiotemporal regulation of antitumor immunity within the TME. At the same time, dendritic cell migration, antigen presentation, CD8[+] T cell infiltration, and T cell exhaustion display time-dependent features that influence the efficacy of immune surveillance and immunotherapy. These findings supported a four-dimensional view of the TME, in which biological timing is a critical determinant of immune competence. We further discussed emerging therapeutic strategies that exploit circadian biology, including small-molecule clock modulators, rhythm-responsive nanomedicine, chronologically optimized CAR-T cell therapy, and time-of-day-dependent immune checkpoint blockade. Although most mechanistic evidence remains preclinical, and many clinical observations are retrospective, current data suggest that treatment timing may be a modifiable, low-cost parameter for improving anti-tumor efficacy while reducing toxicity. Finally, we highlighted future opportunities in microbiome-informed chronotherapy, multi-omics profiling, and digital twin modeling. Integrating temporal information into oncology may shift precision medicine from a static biomarker-driven framework toward a dynamic, time-resolved therapeutic paradigm.

Oral squamous cell carcinoma (OSCC) shows marked biological heterogeneity, but markers that connect malignant epithelial states with the tumor immune context remain limited. Origin recognition complex subunit 6 (ORC6) participates in DNA replication licensing, but its disease-specific role in OSCC is not well defined.