Search Results (593)

Natural killer (NK) cells are key mediators of antitumor immunity; however, NK cell dysfunction in epithelial ovarian cancer should be considered not as a uniform defect, but rather as compartment-specific states that differ across the blood, ascites, primary tumor, and metastatic sites according to their local cellular interactions, soluble factors, and metabolic constraints. Peripheral blood provides an accessible systemic reference and may support immune monitoring. However, it does not fully reflect NK cell states in local or distant disease compartments. In ascites, cytokine-responsive and partially recoverable NK cell populations coexist with soluble, biochemical, and metabolic suppressive signals. In primary tumors, NK cells often acquire tissue-adapted suppressive phenotypes, characterized by altered activating receptors, increased inhibitory checkpoints, and reduced cytotoxic effector function. In metastatic lesions, NK cells appear to share suppressive phenotypes with primary tumors, although these phenotypes may be reinforced within metastatic niches through coordinated inhibitory receptor–ligand interactions. The above compartment-specific states imply that NK cell-targeted therapy for ovarian cancer should not rely on a unilateral strategy. Instead, therapeutic design may need to be multifaceted but coordinated, combining cytokine-based activation, adoptive NK cell transfer, checkpoint blockade, local delivery, and antigen-directed chimeric antigen receptor NK cell approaches according to the dominant biology of each compartment. Paired multi-compartment profiling and longitudinal functional assessment will be essential for biomarker development and compartment-guided treatment design. Full article

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Respiratory mucosal vaccination can induce robust humoral and cellular immune responses, as well as effective mucosal immunity at the primary site of pathogen entry, and has been shown to provide superior protection against respiratory viral infections compared with traditional approaches. Among current vaccine technologies, mRNA vaccines offer unique advantages, including rapid development, flexible antigen design, and potent immunogenicity. However, efficient mucosal delivery of mRNA remains challenging due to biological barriers within the respiratory tract, including mucus clearance, limited cellular uptake, and instability during aerosolization. Furthermore, mRNA formulations intended for respiratory mucosal delivery require more stringent safety and tolerability profiles. Recent advances in nanoparticle engineering have accelerated the development of mRNA delivery systems optimized for respiratory mucosal immunization. This review aims to evaluate how nanoparticle engineering strategies can overcome respiratory mucosal barriers and improve the safety, stability, delivery efficiency, extrahepatic expression, and immunogenicity of mRNA vaccines and therapeutics. We summarize recent progress in engineered mRNA nanoparticle platforms for respiratory mucosal immunity, encompassing modified lipid nanoparticles (LNPs), polymer-based mRNA nanoparticles, and hybrid nanoparticle systems, including lipid-inorganic, polymeric hybrid, and lipid-extracellular vesicle (EV) nanoparticles. We further discuss optimization strategies for mucosal mRNA delivery, including the incorporation of appropriate adjuvants, the development of polyethylene glycol (PEG) alternatives, and advanced delivery approaches. Finally, we highlight current challenges and future directions for the rational design of next-generation mRNA nanoparticle platforms that can induce durable and broadly protective mucosal immunity against respiratory viral infections. Full article

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication in the immune system by transferring proteins, nucleic acids, and lipids. Their biocompatibility, nanoscale size, and capacity for cell-type-selective delivery have stimulated growing interest in engineering EVs as therapeutic platforms. In this review, we discuss recent advances in EV engineering for immune regulation, focusing on surface display, cellular targeting, and cargo loading strategies. A central concept is that engineered EVs should not be viewed simply as delivery vehicles, but as programmable immune interfaces. EVs can integrate antigen specificity, target-cell recognition, therapeutic cargo delivery, and defined immunostimulatory or tolerogenic signals within a single nanoscale particle. By combining these modular elements, engineered EVs can be designed to direct immune responses in a context-dependent manner. We examine how this principle is being applied to cancer immunotherapy, immune suppression, and antigen-specific tolerance induction, including antigen-presenting EVs, cytotoxic and RNA-loaded EVs, checkpoint-modulatory EVs, MSC-derived EVs, and engineered platforms for autoimmune and inflammatory diseases. We also discuss the clinical translation of engineered EV therapeutics, with emphasis on manufacturing, characterization, potency assays, biodistribution, safety, and regulatory challenges. Together, current advances suggest that programmable EV immune interfaces may provide a versatile foundation for next-generation cancer immunotherapy and antigen-specific immune regulation. Full article

Background: Lipopolysaccharide (LPS) functions as a Toll-like receptor 4 (TLR4) agonist that triggers innate immunity; however, structural variations between pathogenic and commensal bacteria distinctly influence its immunostimulatory profile. This study evaluated the immunostimulatory activity of LPS derived from the commensal bacterium Hafnia alvei and explored its potential as an exploratory vaccine adjuvant. Methods: Cytokine induction was evaluated in immune cells across diverse host species, and receptor activation was assessed via reporter assays. To investigate in vivo immunogenicity and preliminary tolerability, H. alvei LPS was formulated into a prototype oil-in-water (O/W) emulsion utilizing ovalbumin (OVA) as a model antigen. Results: LPS from H. alvei strain BA2000346 exhibited immunostimulatory activity comparable to that of Escherichia coli, while inducing greater TNF-α expression than pathogenic Salmonella and Pseudomonas strains. Distinct from E. coli LPS, it demonstrated the capacity to activate both TLR4 and the mannose-recognizing Dectin-2 receptor in reporter systems. This cytokine induction was consistent across various strains and host species. Furthermore, the prototype O/W emulsion formulation enhanced antigen-specific humoral and cellular immune responses while demonstrating preliminary tolerability based on body-weight monitoring and visual clinical observation. Conclusions: H. alvei-derived LPS exhibits TLR4 and Dectin-2 agonist activity in vitro. When synergized with an O/W emulsion delivery system, it provides a preliminary indication of cross-species stimulatory potential and supports further investigation as a hypothesis-generating platform for future vaccine adjuvant development. Full article

While chimeric antigen receptor (CAR)-T-cell therapies have shown significant effectiveness in hematological malignancies, their efficacy in solid tumors remains limited by the hostile tumor microenvironment (TME) and antigen heterogeneity. Recently, CAR-Macrophage (CAR-M) therapy has emerged as a paradigm-shifting approach, leveraging the innate capability of macrophages to deeply infiltrate tumors and their plasticity to reverse immunosuppression. Unlike T cells, CAR-Ms not only mediate direct phagocytosis but also initiate epitope spreading, effectively bridging innate and adaptive immunity. This review critically examines the trajectory of CAR-M therapy from biological rationale to clinical reality. We dissect the engineering evolution of CAR constructs, arguing for macrophage-specific signaling domains (e.g., FcRγ, Megf10) over traditional T-cell designs. Crucially, we address the major bottlenecks in clinical translation, including the manufacturing challenges of non-expanding primary macrophages and the emerging shift toward induced pluripotent stem cell (iPSC)-derived platforms. Furthermore, we evaluate current clinical trial landscapes and discuss next-generation strategies such as in vivo programming via lipid nanoparticles (LNPs) and synthetic logic-gating to enhance safety. Ultimately, overcoming manufacturing constraints and optimizing delivery systems will be pivotal for CAR-M to evolve from a niche therapy into a standard-of-care modality for solid tumors. Full article

The innate–adaptive immune interface is a decisive control point determining whether therapeutic interventions induce durable protection, antitumor immunity, inflammatory, or immune tolerance. Many immunotherapies fail in translation because immunity is often treated as a single-output system rather than a spatially and temporally organized network shaped by tissue context, antigen-presenting cell fate, biomolecular conditioning, and metabolic state. This review introduces the immunoscape framework as a nanobiotechnology-oriented model for linking immune-state mapping with controllable translational variables, including delivery route, release kinetics, first-contact immune cells, lymphatic routing, biomolecular corona identity, antigen-presenting cell fate, and safety-gate assessment. Unlike systems immunology, which primarily describes immune networks, or conventional immune engineering, which often focuses on selected payloads, targets, or platforms, the immunoscape framework provides a design layer for predicting context-dependent immune outcomes. We discuss two converging strategies for reprogramming this interface: natural biologics, including beta-glucans, polyphenols, microbial metabolites, and extracellular vesicles; and smart nanomaterials, including lipid nanoparticles, biomimetic vesicles, lymph node-targeted platforms, and stimulus-responsive nanoarchitectures. We further propose translational design rules to guide clinically realistic immune-reprogramming nanomedicines for cancer, infectious, inflammatory, and regenerative applications. Full article

Nanoemulsion (NEM) is an effective adjuvant and delivery system for vaccines and nucleic acids, capable of inducing immune responses against diverse pathogens. Background/Objectives: Conventional NEM manufacture uses multi-step operations, typically high-shear homogenization and then microfluidization (HSHM), thereby increasing process complexity and contamination risk. As water-rich colloidal dispersions, NEM is prone to microbial proliferation and droplet coalescence; freezing further disrupts microstructure, causing phase fusion and separation, so NEM adjuvants are often stored separately from antigens in multi-vial formats. Lyophilization could reduce cold-chain dependence and enable single-vial products, but there is no systematic study on lyoprotectants comparation and process optimization of lyophilized NEM. Methods: An impingement jet mixing (IJM) process was evaluated as a simplified, scalable route for NEM production. Key IJM parameters, including flow ratio, total flow rate, preparation temperature, microchannel type, and shear mode—were examined to match attributes of conventional HSHM. Lyophilized and reconstituted NEM were characterized by dynamic light scattering, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and/or in vitro potency to inform lyoprotectant selection, and Taguchi Design of Experiment (DOE) methodology guided lyophilization processes. Results: IJM yielded NEM with droplet size, polydispersity index (PDI) and morphology comparable to HSHM, with higher throughput and fewer unit operations. Optimized lyophilization technique with designed lyoprotectant and process formed closed structures to prevent the easy-to-flow monolayer of the emulsion from fusing, producing robust and stable NEM. Conclusions: Coupling IJM with targeted lyophilization establishes a scalable, lower-risk manufacturing paradigm for NEM that preserves critical quality attributes, reduces cold-chain reliance and enables single-vial adjuvanted vaccine formats with tangible industrial and clinical benefits. Full article

The magnitude and quality of adaptive immune responses are fundamentally influenced by the efficiency of antigen presentation. Traditional vaccine platforms, such as live–attenuated or inactivated pathogens, although immunogenic, often present safety concerns. Conversely, subunit vaccines, despite being safer, generally exhibit poor immunogenicity due to inadequate delivery of antigens to professional antigen–presenting cells (APCs). To address this issue, the development of innovative delivery systems has become a pivotal strategy to overcome significant biological barriers, including extracellular antigen degradation, suboptimal lymph node targeting, and inefficient cross–presentation necessary for CD8+ T cell activation. This review systematically explores recent advancements in delivery technologies aimed at enhancing antigen presentation, encompassing rationally engineered nanocarriers and sophisticated biomimetic platforms. We first examine how nanoparticle properties like size, surface charge, and ligand density affect intracellular trafficking and the transition from MHC–II to MHC–I cross–presentation. Then, we explore bioinspired systems such as extracellular vesicles, virus–like particles, and cell–membrane–coated nanoparticles that utilize natural biological traits for enhanced targeting and immune modulation. Additionally, we review new physical delivery methods like microneedle arrays and in situ electroporation for direct, minimally invasive antigen delivery to dendritic cells. Lastly, we discuss the potential of these platforms in personalized cancer vaccines and combination immunotherapies. By combining insights from materials science, immunology, and bioengineering, these next–generation delivery tools could enhance antigen presentation and transform precision vaccination and immune intervention. Full article

In-transit melanoma represents a biologically aggressive form of locoregional disease in which effective management requires integration of local tumor control with systemic immune engagement. Although traditional regional therapies achieve high response rates, they have not consistently translated into durable systemic survival. This review evaluates the clinical development and mechanistic rationale of intralesional therapies, including cytokine-based approaches, oncolytic viruses, immunocytokines, and energy-based delivery platforms, as immunologic intermediaries. Analysis of clinical trial data suggests that outcomes may heavily depend on an agent’s ability to induce immunogenic cell death and sustain antigen presentation. Platforms such as talimogene laherparepvec (T-VEC), vusolimogene oderparepvec (RP1), and tavokinogene telseplasmid with electroporation (Tavo-EP) demonstrate enhanced activity in combination with checkpoint blockade, whereas therapies limited to pattern-recognition receptor activation have shown inconsistent efficacy in randomized trials. Emerging noninvasive technologies, such as focused ultrasound, may further expand strategies for remodeling the immunosuppressive tumor microenvironment to enable immune sensitization. These findings support a shift toward mechanism-based treatment selection in which locoregional therapies function to overcome immune resistance rather than solely reduce tumor burden. Full article

Normal prostate epithelial cells accumulate high intracellular zinc levels that maintain optimum mitochondrial metabolism and proliferation. Prostate cancer cells lose this zinc-accumulating capacity, enabling metabolic reprogramming that supports tumor progression. Restoring intracellular zinc selectively in prostate tumors represents a promising therapeutic strategy; however, systemic zinc administration is limited by the inability of prostate cancer cells to take up free zinc resulting from ZIP1 transporter downregulation. To overcome this challenge, we developed a formulation of prostate-specific membrane antigen (PSMA)-targeted, zinc-loaded liposomes (Zn-TL) to enable tumor-selective intracellular zinc delivery. Zn-TL was prepared with uniform nanoscale size, low polydispersity, and negative surface charge. The formulation showed minimal zinc leakage during storage and sustained retention in vitro. In prostate cancer cells, Zn-TL demonstrated receptor-mediated uptake, resulting in increased cytotoxicity and apoptosis. In vivo, we performed proof-of-principle studies showing prolonged circulation and tumor accumulation of Zn-TL in mice bearing PSMA-positive tumors. While tumor growth was delayed during early and intermediate stages of tumor development, this effect diminished at later stages. The stage-dependent efficacy suggests that Zn-TL may be most effective when used earlier in disease progression. These results also suggest that Zn-TL represents a promising platform for metabolic intervention and may benefit from combination strategies to enhance efficacy in advanced disease. Full article

Developing potent adjuvants is critical for enhancing vaccine efficacy, particularly for subunit antigens. Background/Objectives: This study evaluates a novel composite adjuvant system combining liposomal QS-21 and CpG ODNs to enhance vaccine-induced immunogenicity, particularly Th1-type cellular immunity. Methods: To mitigate QS-21’s hemolytic toxicity and ensure precision delivery, a stable liposomal formulation was developed. Mice models were established using varicella-zoster virus (VZV) glycoprotein E (gE) or ovalbumin (OVA) as antigens to evaluate humoral and cellular immune responses. Results: Immunization with gE protein formulated with this novel adjuvant synergistically triggered robust immune responses, outperforming single adjuvants and the combination of QS-21/MPL. Across broad dose ranges, it induced higher Th1-type cellular immunity and comparable humoral immunity relative to AS01_B. Mechanistic studies revealed that the adjuvant significantly enhances the recruitment of dendritic cells (DCs), monocytes, and neutrophils to draining lymph nodes (dLNs) while upregulating co-stimulatory molecules CD40 and CD86 on DCs. Furthermore, the formulation triggered robust, transient increases in Th1-associated cytokines (IFN-γ, IL-12) and chemokines (CXCL9, CXCL10) across the injection site, serum, and dLNs. Conclusions: These findings indicate that the liposomal QS-21 and CpG ODNs system is a highly effective platform for promoting robust Th1-biased immunity, offering a promising adjuvant candidate and a solid experimental foundation for developing next-generation vaccines requiring potent cellular immunity. Full article

Vaccination remains one of the most effective strategies for preventing infectious diseases. Yet, the success of modern vaccines increasingly depends on the rational design of adjuvants that enhance and shape immune responses. In this review, we examine current and emerging adjuvant strategies for viral vaccines across the human lifespan. Traditional adjuvants, particularly aluminum salts, have long served as the foundation of vaccine formulations. Still, their limitations have driven the exploration of novel platforms, including emulsions, nucleic acid-based adjuvants, and advanced particulate delivery platforms with intrinsic immunostimulatory properties. These newer approaches act through diverse mechanisms, such as activating innate immune pathways via pattern recognition receptors (PRRs) and stimulating antigen-presenting cells (APCs), thereby improving both humoral and cellular immunity. Recent advances in molecular biology, nanotechnology, and systems vaccinology have deepened mechanistic understanding and enabled more precise modulation of immune responses. However, significant challenges remain, including incomplete knowledge of adjuvant mechanisms, limited diversity among licensed adjuvants, safety concerns, and inconsistent efficacy across age groups. In particular, immune immaturity in infants and immunosenescence in older adults highlight the need for age-specific adjuvant strategies. The review identifies critical gaps in comparative studies, long-term safety data, and the development of adjuvants capable of inducing broad and durable immunity. Further, this article integrates licensed and emerging viral vaccine adjuvants through a lifespan framework. Addressing these limitations through interdisciplinary research and precision-based approaches will be essential for advancing next-generation vaccines and improving global preparedness for emerging infectious diseases. Full article

Systemic administration of antibodies that target immune checkpoint inhibitor pathways is a highly effective approach to cancer immunotherapy, but systemic toxicity can limit clinical utility. In preclinical testing, a peri-tumor injection of a low dose of hydrogel-encapsulated cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody was shown to selectively activate T cells in tumor-draining lymph nodes, induce tumor infiltration by cytotoxic T cells, and result in tumor regression, protective immunity, and long-term survival. In contrast to systemic therapy, there was limited systemic exposure or risk for autoimmune toxicity. The current study focuses on translating this platform into a biocompatible human therapeutic. The hydrogel matrix was reformulated using a low-molecular-weight hyaluronic acid. A recombinant human hyaluronidase (rHuPH20) was incorporated to promote lymph node targeting and self-resorbing features. Formulations were optimized to operate at neutral pH and with gelation kinetics allowing a 5 to 10 min administration window. Performance features were assessed including the capacity to encapsulate human IgG or ipilimumab antibody at proposed therapeutic doses (1–15 mg/mL), impact of rHuPH20 and antibody on rheologic properties and three-dimensional microstructure, and payload delivery profiles in vitro and in vivo. Results confirm the capacity for this unique hydrogel platform to be adapted for human testing. Full article

Therapeutic cancer vaccines are a promising immunotherapy approach in genitourinary (GU) cancers, designed to stimulate antitumor immune responses through antigen-specific T-cell activation. Although agents such as bacillus Calmette–Guérin in bladder cancer and sipuleucel-T in prostate cancer have shown success, vaccine monotherapy has generally produced limited clinical benefit due to tumor heterogeneity, poor immune infiltration, and immunosuppressive tumor microenvironments. Multiple vaccine platforms have demonstrated safety and immunogenicity in prostate, renal cell, and urothelial cancers, but efficacy remains modest. Current strategies focus on multi-antigen targeting, improved antigen presentation, and combination therapies with immune checkpoint inhibitors, radiotherapy, and targeted agents to enhance antitumor activity. Advances in personalized vaccine design and delivery systems are driving progress, though challenges such as manufacturing complexity, cost, and biomarker development remain. Ongoing translational and clinical research will be critical to improving the effectiveness of vaccine-based immunotherapy in GU malignancies. Full article