Search Results (719)

Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a “double-edged sword” that greatly influences the success of immune checkpoint inhibitors (ICIs). On the one hand, RT acts like an in situ vaccine, causing immunogenic cell death and activating the cGAS-STING pathway, which leads to dendritic cell maturation, T-cell infiltration, and reactive PD-L1 expression. This effect can turn “cold” tumors into “hot” ones, making them more responsive to immune checkpoint blockade. On the other hand, RT can lead to resistance to ICIs by promoting an immunosuppressive environment, recruiting regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. This review analyzes the mechanisms behind this immunological duality and assesses how parameters such as dose, fractionation, and particle type (e.g., carbon ion versus photon therapy) can be optimized to enhance immune activation. Lastly, we discuss future strategies that focus on innate immunity and tumor metabolism, showing how targeting nutrient depletion and ferroptosis can break down immunosuppressive barriers and position RT as an essential component of precision immuno-oncology. Full article

Photodynamic therapy (PDT) occupies an important place in the arsenal of cancer treatment modalities; however, its efficacy is primarily limited by the local nature of its effects and by tumor cell resistance. The aim of this review is to analyze the fundamental principles and biological consequences of PDT, to summarize current data on the molecular and cellular mechanisms determining its efficacy, and to consider strategies for overcoming its limitations. Particular attention is paid to the mechanisms underlying resistance development and to the role of switching from non-immunogenic to immunogenic cell death in shaping the antitumor response. The potential integration of PDT with dendritic cell vaccination is considered a promising strategy for overcoming these limitations. The potential of vaccine-based approaches to activate specific antitumor immunity in aggressive cancers is highlighted, with emphasis on the advantages of dendritic cell vaccines in addressing the limitations of conventional PDT. Full article

Bone metastases remain one of the most clinically devastating complications of advanced cancer, particularly in breast, prostate, and lung malignancies, where they drive pain, fractures, hypercalcemia, and progressive functional decline. Their management is further complicated by a highly immunosuppressive bone microenvironment characterized by osteoclast-driven bone destruction, myeloid cell dominance, impaired antigen presentation, and weak effector T-cell infiltration, all of which limit the activity of conventional immunotherapies. In this setting, nanoparticles are emerging not merely as passive drug carriers but as programmable platforms capable of reshaping the metastatic niche. This review discusses how bone-targeted and immune-responsive nanocarriers can improve therapeutic precision through hydroxyapatite-binding ligands, dual-targeting strategies, stealth coatings, enzyme- and pH-responsive release systems, and externally guided platforms. We further examine how these systems modulate key immune compartments within bone metastases, including reprogramming tumor-associated macrophages and myeloid-derived suppressor cells, restoring cytotoxic T-cell activity, enhancing dendritic-cell activation, and enabling in situ vaccination through photothermal or photodynamic immunogenic cell death. Particular attention is given to the delivery of checkpoint inhibitors, cytokines, siRNA/miRNA, mRNA, and clustered regularly interspaced short palindromic repeats (CRISPR)-based payloads, as well as to the rational combination of these with chemotherapy, bone-modifying agents, and radiotherapy. Finally, we highlight major translational barriers, including lesion heterogeneity, limited penetration into mineralized tissue, off-target immune effects, manufacturing complexity, and the continued lack of bone-specific preclinical and clinical validation. Collectively, immunomodulatory nanoparticles represent a promising strategy to convert bone metastases from immune-refractory sites into more therapeutically responsive lesions. Full article

Dendritic cells (DCs) are central to cancer immunity, orchestrating both innate and adaptive immune responses. In melanoma and other solid tumors, however, their function is often impaired within the tumor microenvironment (TME), leading to weakened antitumor immunity and diminished responses to immune checkpoint inhibitors (ICIs) and adoptive tumor-infiltrating lymphocyte (TIL) therapy. Among the various cell-based immunotherapy approaches, DC therapy—particularly using blood-derived conventional DCs (cDCs)—holds considerable promise. Compared with traditional monocyte-derived DCs (moDCs), cDCs exhibit superior antigen processing and cross-presentation capacities. The therapeutic application of cDCs was initially pioneered in vaccine strategies involving ex vivo antigen loading and maturation, followed by administration to lymph nodes. More recently, intratumoral (IT) cDC immunotherapy has emerged as a strategy to reinvigorate the cancer-immunity cycle by engaging the full repertoire of tumor-associated antigens while limiting systemic toxicity. This review discusses the underlying biological mechanisms and summarizes the clinical outcomes of IT DC therapy in cancer. Notably, combination approaches incorporating IT cDCs with ICIs, oncolytic viruses, synthetic adjuvants, radiation, or cryotherapy are emerging as promising strategies to overcome both primary and acquired resistance to ICI monotherapy. Collectively, these findings highlight the potential of integrating IT cDC therapy with complementary immunotherapies in next-generation, cross-tumor treatment strategies. Full article

Background/Objectives: Whole-cell vaccines have demonstrated clinical potential in cancer treatment and recurrence prevention, yet their immunogenicity and dendritic cell (DC) activation remain suboptimal. This study aimed to evaluate whether a needle-free injector (NFI) could enhance the immunogenicity and antitumor efficacy of whole-cell tumor vaccines. Methods: Adaptive immune responses induced by NFI and traditional syringe injection (SYI) were compared following whole-cell vaccine administration. The morphology of vaccine fluid ejected by NFI and SYI was examined, and the effects on DC antigen uptake and activation were assessed. Antitumor efficacy was further evaluated in MC38 colon adenocarcinoma challenge models. Results: NFI administration elicited stronger antigen-specific adaptive immune responses than SYI. The high-velocity pressure generated by NFI resulted in fragmentation of whole-cell vaccine material, and this morphological alteration was associated with enhanced DC antigen uptake and activation. These immunological improvements corresponded with superior tumor suppression in MC38 models following NFI-delivered vaccination. Conclusions: NFI delivery enhances the immunogenicity and antitumor efficacy of whole-cell tumor vaccines. These findings suggest that needle-free injectors may serve as a simple and effective strategy to improve the performance of whole-cell cancer vaccines. Full article

Hapten-based immunotherapies represent a promising strategy to enhance the immunogenicity of tumor antigens and promote antitumor immune responses. Chemical conjugation of small haptens to antigens generates novel antigenic determinants that increase immune recognition. Mechanistic studies indicate that haptenation enhances antigen uptake, dendritic cell maturation, and the activation of both cellular and humoral immunity. In preclinical models, hapten-modified antigens induce robust immune activation, tumor regression, and durable immune memory. Clinically, dinitrophenyl-modified autologous tumor cell vaccines elicit delayed-type hypersensitivity responses and clonal T-cell expansion, with evidence of clinical activity and a favorable safety profile. However, their clinical benefit remains to be confirmed in larger, randomized studies. Emerging strategies include in situ haptenation and bihaptenized or stressed hapten-modified allogeneic platforms, which aim to expand epitope diversity and enhance immune priming. Hapten-based immunotherapies offer a clinically feasible approach to converting poorly immunogenic tumors into effective immune targets. Full article

Background/Objectives: High-grade serous ovarian cancer (HGSOC) is usually discovered in advanced stages and often relapses shortly after initial conventional therapy. Survival in HGSOC patients might be improved with the use of novel immune therapies, which potentiate autologous anti-tumor responses. Dendritic cells (DCs) are potent antigen-presenting cells that can initiate immune responses, activate cytotoxic T cells and drive T-cell differentiation. This pilot trial evaluated the safety and efficacy of a unique DC vaccine (α-DC-1) in relapsed, advanced HGSOC patients with minimal tumor burden. Methods: Monocytes from patient leukaphereses were used to propagate a unique autologous DC, the α-DC-1, generated with granulocyte–macrophage colony-stimulating factor and interleukin-4, pulsed with keyhole limpet hemocyanin (KLH) and tumor lysate (from debulking surgery) on day 5, and matured with a cocktail of cytokines and chemokines on day 6. Mature α-DC-1 were harvested on day 7 and administered intranodally (inguinal nodes) every other week for three doses/cycle for up to three DC vaccine cycles (nine vaccines). The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: In 19 patients treated, the median PFS was 9.7 months (95% CI: (5, NA)) and the median OS was 42.2 months (95% CI: (31.2, 68.3)). In 5/19 (26.3%) patients, OS exceeded five years. Administration of six or more vaccines was associated with a significant improvement in PFS. No grade 2 or higher toxicities were noted. Conclusions: Our α-DC-1 vaccine was safe, and 94.2% elicited an immune response to KLH. The long OS, exceeding 5 years in some patients, suggests this DC vaccine may improve survival for some with relapsed HGSOC. Full article

Background: Non-typeable Haemophilus influenzae (NTHi) is a major cause of acute respiratory tract infections and chronic airway disease, despite its clinical importance, no licensed vaccine is available, largely due to the extensive genetic and antigenic diversity among circulating isolates. We previously identified conserved outer membrane proteins capable of inducing systemic protection against NTHi. Methods: In this study, we evaluated whether a multi-antigen protein vaccine composed of conserved NTHi antigens (P5 and P26) could protect against pulmonary infection. Transgenic mice expressing human transferrin and factor H were immunized via the intraperitoneal or intranasal route and challenged intranasally with a clinical NTHi isolate. Bacterial clearance, antigen-specific mucosal and systemic antibody responses, and recruitment of innate immune cells to the airways were assessed. Results: Both immunization routes significantly reduced bacterial loads compared with controls. Vaccination induced robust mucosal and systemic IgG and IgA responses and enhanced early recruitment of macrophages, monocytes, dendritic cells, and neutrophils to the airways. Intranasal immunization elicited strong mucosal antibody responses and was associated with improved local bacterial clearance. Conclusions: These findings demonstrate that multi-antigen vaccines targeting conserved NTHi proteins can elicit effective mucosal and systemic immunity and represent promising candidates for the prevention against NTHi respiratory infections. Full article

Objectives: This study aimed to investigated the role of Giardia extracellular vesicles (EVs) in intercellular communication and to evaluated their potential as vaccine candidates. Methods: The immunomodulatory effects of Giardia EVs were assessed in mouse macrophages and human monocyte-derived dendritic cells (Mo-DCs), with a particular focus on key inflammatory signaling pathways. In vivo immunogenicity was evaluated following EV administration, and the antigenic composition of EV cargo was characterized by proteomic analysis. Results: Giardia EVs activated pro-inflammatory signaling pathways in mouse macrphages, including SAPK/JNK, ERK1/2, and NF-κB. This activation was associated with IκB-α degradation and nuclear translocation of p65. Furthermore, EV stimulation significantly upregulated the expression of pro-inflammatory genes, including Il1β, Il6, Il4, Ptgs2, Nos2, and Tnf, with log₂ fold changes ranging from 3.9 to 15.8. Consistently, EVs increased iNOS protein expression (28–45%) and nitrite production (9.6–12.3-fold). In human Mo-DCs, Giardia EVs promoted cellular maturation, as evidenced by increased expression of MHC-II, CD80, and CD86, and enhanced T-cell proliferation with a Th1-skewed profile. In vivo immunization induced antigen-specific antibody responses, with IgG subclass distribution indicative of a balanced Th1/Th2 response. Proteomic analysis identified immunoreactive EV-associated proteins, including elongation factor 1-alpha, α-7.3 giardin, tubulin, and variant surface proteins (VSPs), which are well-established antigens in Giardia infection, with prominent bands observed at approximately 22 kDa and 50 kDa. Conclusions: Collectively, these findings demonstrate that Giardia EVs modulate innate immune responses in vitro, elicit antigen-specific humoral immunity in vivo, and contain conserved immunogenic proteins. These properties support their potential as a promising cell-free vaccine platform against giardiasis. Full article

Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted predominantly through the bite of infected Hyalomma ticks, yet the earliest events at the vector–host–virus interface in human skin remain largely undefined. This review synthesizes current knowledge of human cutaneous structure and immunity, tick feeding biology, and salivary immunomodulation to propose how local skin responses may shape systemic outcomes of CCHFV disease. We detail the roles and permissiveness of major skin-resident and infiltrating cell types, including keratinocytes, melanocytes, Langerhans cells, dermal dendritic cells, monocytes/macrophages, fibroblasts, granulocytes, T cells, B cells, NK cells, and innate lymphoid cells, in antiviral defense and as potential early targets or carriers of CCHFV. Emphasis is placed on how tick saliva components reprogram the cutaneous microenvironment, alter interferon, complement, inflammasome, and cytokine pathways, and may enable saliva-assisted transmission and viral dissemination from the dermis. We highlight mounting evidence from other arboviruses demonstrating that the skin can act as both a barrier and a major amplifying organ, and we extrapolate testable hypotheses on how early cutaneous immune dynamics might influence CCHFV severity and hemorrhagic manifestations. Finally, we outline key knowledge gaps that, if answered, may inform the development of vaccines and therapeutics that harness cutaneous immunity to block systemic spread. Full article

Immunogenic cell death (ICD) links tumor cell demise to the activation of anti-tumor immunity, but its adoption has also generated inconsistent definitions and frequent overinterpretation of surrogate biomarkers. Here, we synthesize mechanistic and methodological evidence showing that danger-associated molecular patterns (DAMPs), cytokine release, and endoplasmic reticulum stress report immunogenic potential rather than ICD itself. We propose that ICD should be defined by its functional immunological endpoint, namely efficient antigen presentation and antigen-specific adaptive immunity, ideally culminating in protective immunological memory. To operationalize this principle, we introduce a hierarchy of experimental validation ranging from correlative hallmarks (Level 0) to innate immune integration (Level 1), antigen-specific T-cell priming (Level 2), definitive vaccination-rechallenge protection with immune-dependence testing (Level 3), and translational relevance supported by convergent human data (Level 4). We also discuss common pitfalls, equating inflammation, necrosis-associated DAMP release, or therapeutic benefit with ICD, and outline minimal immune-context controls (e.g., MHC-I, CD8⁺ T cells, Batf3-dependent dendritic cells, and innate sensing pathways) required to support robust claims. Finally, we highlight why ICD remains strongly context-dependent, shaped by dendritic-cell competence, innate licensing, purinergic metabolism, and microenvironmental constraints. Evidence-graded standards should improve reproducibility, strengthen peer review, and accelerate clinically meaningful ICD-based strategies. Full article

The α-gal epitope is synthesized in non-primate mammals and New-World monkeys by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT), encoded by the GGTA1 gene. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent extinction 20–30 million years ago. Their mutated offspring, with the inactivated GGTA1 gene, survived and produced the natural anti-Gal antibody, specifically binding α-gal epitopes. Anti-Gal protected the surviving offspring from lethal viruses presenting α-gal epitopes, which killed α-gal-synthesizing parental primates. Anti-Gal constitutes ~1% of human immunoglobulins and is also produced in Old-World monkeys and apes. α-Gal epitopes can serve as therapeutic agents in several clinical disciplines: 1. Cancer immunotherapy: Engineering cancer cells to express α-gal epitopes results in anti-Gal binding to these cells and localized activation of the complement system that kills these cancer cells and recruits the antigen-presenting cells (APCs) dendritic cells and macrophages. Anti-Gal bound to cancer cells targets them for robust uptake by APCs, which process internalized tumor antigens (TAs) and transport them to lymph nodes for activation of cytotoxic T-cells. These T-cells kill TA-presenting metastatic tumor cells. Clinical trials demonstrated that such engineering is achieved by intra-tumoral injection of α-gal glycolipids, the use of recombinant α1,3GT, or the use of oncolytic viruses containing the GGTA1 gene. 2. Viral vaccines: Inactivated whole-virus vaccines presenting α-gal epitopes bind anti-Gal, which targets them for extensive uptake by APCs, thereby increasing their immunogenicity by ~100-fold. 3. Injured-tissue regeneration: Anti-Gal binding to α-gal-presenting nanoparticles administered to wounds, into the post-myocardial infarction (MI) injured myocardium and into injured spinal cord, activates the complement system that recruits pro-regenerative macrophages, which orchestrate regeneration by recruiting stem cells and the secretion of pro-regenerative cytokines. All these findings suggest that α-gal/anti-Gal antibody interaction can serve as a novel therapeutic approach, applicable to various clinical settings. Full article

Trained immunity confers protection against subsequent unrelated infections through metabolic and epigenetic reprogramming. Unlike adaptive immunity, trained innate immunity provides broad, non-specific protection against diverse heterologous pathogens. In addition to potentiating inflammatory responses upon secondary challenge, trained innate immune cells can also acquire anti-inflammatory and tolerogenic phenotypes, a property with important implications for chronic inflammatory diseases such as allergic disorders. Trained immunity-based vaccines (TIbVs) have emerged as promising immunomodulatory strategies capable of attenuating allergic inflammation by inducing immune tolerance. Similarly, allergen-specific immunotherapy (AIT) promotes long-term tolerance to allergens through metabolic and epigenetic reprogramming of innate immune cells. AIT drives the differentiation of monocytes into tolerogenic dendritic cells, thereby reshaping downstream adaptive immune responses. This review summarizes the current understanding of trained immunity and its role in protection against the same and heterologous infections. We discuss the molecular mechanisms underlying trained immunity, with an emphasis on metabolic and epigenetic reprogramming. Furthermore, we highlight the therapeutic potential of TIbVs and AIT as next-generation vaccines for allergic diseases. A deeper understanding of AIT-induced immune tolerance, the identification of predictive biomarkers, and the optimization of delivery platforms—such as lipid nanoparticle-based systems—will be critical for improving the safety and efficacy of future anti-allergy vaccines. Full article

Herpes simplex virus type 2 (HSV-2) is the primary pathogen responsible for genital herpes. Predominantly transmitted via sexual contact, HSV-2 not only poses significant physical and psychological burdens on infected individuals but also substantially elevates the risk of HIV acquisition and represents a potentially fatal threat to newborns. Following primary infection, HSV-2 establishes lifelong latent infection within the sacral ganglia. Currently, there are no vaccines or therapeutics capable of eradicating this latent virus reservoir or effectively preventing initial infection. The core impediment to developing such interventions lies in the incomplete elucidation of the protective immune mechanisms against HSV-2 and its precise molecular pathogenesis. The host immune response against HSV-2 hinges critically on the coordinated interplay between innate and adaptive immunity. The innate immune system, serving as the first line of defense, acts to curtail early viral replication and initiate adaptive responses. This is achieved through mechanisms, including the genital mucosal barrier, activation of Toll-like receptors (TLRs), the cGAS-STING signaling pathway, interferon (IFN)-mediated antiviral effector functions, and activation of innate immune cells such as natural killer (NK) cells and dendritic cells (DCs). Crucially, however, HSV-2 counteracts these host defenses by expressing immune modulatory proteins (e.g., ICP0, ICP27, ICP35) that target key host antiviral signaling pathways, thereby affecting immune evasion. Within the adaptive immune response, neutralizing antibodies generated by the humoral immunity can provide localized protection at mucosal sites, but their protective efficacy is limited due to sophisticated viral immune evasion mechanisms. Cellular immunity, particularly mediated by CD4+ T cells, constitutes the core mechanism for viral clearance and suppression of recurrent outbreaks. Notably, tissue-resident memory T cells (TRMs) play a pivotal role in controlling the reactivation of latent HSV-2 within the ganglia. This review integrates current research advances to delineate the innate and adaptive immune mechanisms engaged during HSV-2 infection from the perspective of the dynamic host–virus interplay, with an ultimate aim to provide a theoretical foundation informing the rational development of preventive vaccines and therapeutic agents against HSV-2. Full article

Background: Latent tuberculosis infection (LTBI) is the principal reservoir for active tuberculosis, with >85% of cases attributable to reactivation. Bacillus Calmette-Guérin fails to block this transition, leaving a critical gap in prevention. Methods: An immunoinformatics/reverse-vaccinology pipeline was applied to seven dormancy-related antigens retrieved from Mycobrowser. T-cell epitopes were predicted with NetMHCI/IIpan-4.1 and B-cell epitopes with ABCpred; antigenicity, allergenicity, and toxicity were evaluated with VaxiJen, AllerTOP, and ToxinPred. Secondary/tertiary structures were modeled with PSIPRED and AlphaFold-3; docking to Toll-like receptors (TLR) 2/4 and 100 ns molecular dynamics simulations assessed complex stability. Immune responses were simulated with C-ImmSim, and the mRNA sequence was human-codon-optimized using ExpOptimizer. Results: The resulting construct, RP14914P, encodes 14 cytotoxic T lymphocyte, 9 helper T lymphocyte, and 14 B-cell epitopes within an 866-aa, 90.4 kDa polypeptide. Antigenicity score = 0.7797, immunogenicity score = 8.58629. and no toxicity or allergenicity was predicted. Physicochemical analysis: instability index = 28.65, and solubility = 0.513. Estimated population coverage is 82.35% and 99.67% for Human Leukocyte Antigen (HLA)-I and HLA-II globally. Docking energies: −1477.8 kcal/mol (TLR2) and −1480.1 kcal/mol (TLR4). Molecular dynamics trajectories confirm stable binding. Immune simulation predicts potent activation of Natural Killer cells, macrophages, and dendritic cells, Th1 polarization, high interferon-γ/interleukin-2 secretion, and durable memory. Conclusions: In silico analyses predict that RP14914P exhibits favorable immunogenicity, safety, and broad population coverage, suggesting its potential as a promising mRNA vaccine candidate to prevent LTBI reactivation. However, these computational predictions require thorough experimental validation to confirm the vaccine’s immunogenicity and protective efficacy. Full article