Nanocarriers can improve the therapeutic efficiency of small molecule immunomodulators or inhibitors, which is important for immunotherapy of liver diseases or cancer. Macromolecular protein carriers, such as human serum albumin (HSA), could provide better penetration compared to large nanoparticles (>50 nm) but are hampered by systemic biodistribution. To overcome these limitations, inspired by the natural glycogen structure, we have designed the HSA nanocarrier (<40 nm) consisting of multiple trimannose (TM) ligands attached to the protein surface, to target mannose or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptors in immune cells or immunological organs such as the liver. Capitalizing on the chemical reactivity of different amino acids present in HSA, we have incorporated multiple copies of a cargo relevant for immunotherapy, i.e. the toll-like receptor (TLR) 7/8 agonist. The resulting TM-HSA conjugates exhibit excellent and specific uptake ex vivo in various immune cells and liver-specific uptake in vivo, opening access to protein nanocarriers with rapid and efficient in vivo targeting with great potential for immune-related diseases.

Melanoma, driven by defective immune surveillance and cancer-cell evasion, has rising morbidity and mortality due to solar radiation exposure and delayed diagnosis. Effective tumor opsonization and phagocytosis are needed, demanding new therapeutic formulations. Here, we demonstrate the efficacy of a novel lipid-coated glucose nanosphere (LGNP) formulation decorated with ovalbumin (OVA) and containing pCMV-MART-1 (MT-1), termed the nLOM vaccine. This vaccine elicits specific immune responses through bone marrow DC maturation and CD4+/CD8+ T-cell activation, targeting melanoma antigens. In preclinical studies using orthotopic B16-F10 melanoma cells in C57BL/6J mice, the vaccine induced significant infiltration of T lymphocytes into tumor tissues, reducing tumor progression. Robust immune responses were observed in the spleens and inguinal lymph nodes of vaccinated mice, characterized by elevated cytokine levels. These findings suggest that the nLOM vaccine could elicit durable immunogenicity against melanoma through enhanced antigen presentation and holds promise for clinical development as an effective immunotherapy.

In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

The immunogenicity of rabies vaccines is commonly measured by serological testing, which includes measuring rabies virus-neutralising antibody titre levels in the serum. Apart from humoral immunity, cellular immunity measurements are also helpful in assessing the immunogenicity and efficacy of rabies vaccinations. Recently, there has been an increased emphasis on cellular immunity measurements against rabies in humans and animals. This review aimed to systematically analyse the literature on the composition of cellular immune responses against rabies vaccination in laboratory dogs. A literature survey was conducted to collect suitable articles by searching the research databases PubMed, Web of Science and Scopus. Subsequently, a two-person screening was conducted to identify suitable articles based on predetermined inclusion and exclusion criteria. Data extraction was performed by two authors independently. A total of 1396 studies were identified from the initial search. Following the screening, six studies were selected for final review. Different methods of detecting immune parameters from peripheral blood mononuclear cells were identified from the studies. Reports have demonstrated positive outcomes of the use of adjuvants for cellular immunity development. Even though the lack of specific immunological techniques and the specific reagents have negatively affected these types of cellular immunity measurements, it was evident that combining both humoral and cellular immune parameters against the rabies antigen would provide a clearer picture of the level of responsiveness in animals towards vaccinations and the protection against the disease. The protocol for this review was published in the International Prospective Register of Systematic Review (CRD42022380023).

Septicemia triggers a profound systemic inflammatory response, ultimately leading to cellular senescence. Understanding the mechanisms underlying intercellular interactions associated with sepsis is crucial for developing therapeutic strategies targeting sepsis and its associated complications. Neonatal septicemia (NS) is a critical condition characterized by systemic infection in newborns. Currently, there are no effective indicators for the early identification of sepsis and precise screening of newborns who truly require antibiotic treatment, which results in delayed diagnosis of neonatal sepsis and the overuse of antibiotics. We aimed to elucidate cellular senescence-related genes (CSRGs) in the context of NS and to investigate their potential regulatory networks and immune infiltration patterns. Our analysis identified 391 DEGs, including 301 upregulated and 90 downregulated genes and 15 differentially expressed CSRGs (CSRDEGs), including STAT3, MAPK14, IGFBP7, PPARG, and ETS2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed enrichment in biological processes, including cellular senescence, and pathways involving PD-L1 expression in cancer. Gene Set Enrichment Analysis highlighted significant pathways, including selenoamino acid metabolism and neutrophil degranulation. Protein-protein interaction network analysis identified eight hub genes: STAT3, MAPK14, CEBPB, TLR2, ETS1, JUNB, PPARG, and MAP3K5. Regulatory network analysis revealed interactions between CSRDEGs and multiple transcription factors/miRNAs. Immune infiltration analysis revealed profound differences in the composition of immune cells between the normal and NS groups. Our study findings offer valuable information for future research on therapeutic targets and diagnostic markers of NS.

Nanoparticle-based drug delivery systems hold promise for tumor therapy; however, they frequently encounter challenges such as low delivery efficiency and suboptimal efficacy. Engineered living cells can redirect drug delivery systems to effectively reach targeted sites. Here, we used living macrophages as vehicles, attaching them with GeS nanosheets (GeSNSs) carrying β-elemene for transport to tumor sites. GeSNSs act as efficient sonosensitizers, enhancing ultrasound-induced reactive oxygen species generation for treating 4T1 breast tumors. Notably, macrophage hitchhiking delivery of β-elemene-loaded GeSNSs not only achieves high accumulation in tumor regions and suppresses tumor growth under ultrasound treatment, but also effectively remodels the immunosuppressive tumor microenvironment by improving M1-like macrophage polarization and enhancing the populations of mature dendritic cells, CD4+, and CD8+ lymphocytes, thereby facilitating enhanced sonodynamic chemoimmunotherapy. These findings underscore the potential of macrophage hitchhiking strategy for drug delivery and suggest broader applicability of engineered living materials-mediated delivery technologies in disease therapy.

Immune system plays a crucial role in the physiological and pathological regulation of the cardiovascular system. The exploration history and milestones of immune system in cardiovascular diseases (CVDs) have evolved from the initial discovery of chronic inflammation in atherosclerosis to large-scale clinical studies confirming the importance of anti-inflammatory therapy in treating CVDs. This progress has been facilitated by advancements in various technological approaches, including multi-omics analysis (single-cell sequencing, spatial transcriptome et al.) and significant improvements in immunotherapy techniques such as chimeric antigen receptor (CAR)-T cell therapy. Both innate and adaptive immunity holds a pivotal role in CVDs, involving Toll-like receptor (TLR) signaling pathway, nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) signaling pathway, inflammasome signaling pathway, RNA and DNA sensing signaling pathway, as well as antibody-mediated and complement-dependent systems. Meanwhile, immune responses are simultaneously regulated by multi-level regulations in CVDs, including epigenetics (DNA, RNA, protein) and other key signaling pathways in CVDs, interactions among immune cells, and interactions between immune and cardiac or vascular cells. Remarkably, based on the progress in basic research on immune responses in the cardiovascular system, significant advancements have also been made in pre-clinical and clinical studies of immunotherapy. This review provides an overview of the role of immune system in the cardiovascular system, providing in-depth insights into the physiological and pathological regulation of immune responses in various CVDs, highlighting the impact of multi-level regulation of immune responses in CVDs. Finally, we also discuss pre-clinical and clinical strategies targeting the immune system and translational implications in CVDs.

Although alopecia areata (AA) is recognized as a hair loss disorder stemming from the dysregulation of cutaneous immune homeostasis, its precise pathogenesis still remains elusive. The collapse of hair follicle (HF) immune privilege (IP), leading to immune cell-mediated attack on the hair follicle, is currently the widely accepted fundamental mechanism of AA. Among the immune cells studied in this context, CD8+ T cells and regulatory T (Treg) cells are relatively well-researched, but the direct involvement of macrophages in the disease process has been less frequently demonstrated. In this review, we summarize various previous studies on macrophages and hypothesize the immune mechanisms by which macrophages contribute to the pathogenesis of AA. This exploration provides new insights for future research and potential clinical treatments.

The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome treatment resistance.

We conducted an in vivo chemical screen to identify F1929-1458, which is capable of eliciting an organism-wide response to destroy stem cell tumors in Drosophila. We then performed functional validation using a mouse colorectal cancer graft tumor model established with the CT26 cell line characterized by its high content of CSCs. Single-cell sequencing was employed to analyze alterations in the TME. Small molecule pull-down mass spectrometry, cellular thermal shift assay, drug affinity experiment, and molecular docking were utilized to identify the target of F1929-1458. An in vitro co-culture system was applied to establish that the damage-associated molecular patterns (DAMPs) released by the tumor cells are accountable for the activation of dendritic cells (DCs).

We demonstrated that F1929-1458 treatment enhanced T cell infiltration and T cell mediated tumor regression, its anti-tumor effect was nullified in nude mice and was abolished after anti-CD3 neutralizing antibody treatment. We found that F1929-1458 binds NFKB1 to activate the NF-κB signaling pathway in tumor cells. The activation further elicits cellular stress, causing tumor cells to release DAMPs (HMGB1-gDNA complex, ATP, and OxLDL). These DAMPs, in turn, stimulate the cGAS-STING and NLRP3 inflammasome pathways in DCs, resulting in the generation of type I IFNs and IL-1β. These cytokines facilitate the maturation of DCs and antigen presentation, ultimately enhancing T cell-mediated anti-tumor immunity. Additionally, we showed that the combination of F1929-1458 and the anti-PD-1 antibody exhibited a synergistic anti-tumor effect.

Our study identified a novel NFKB1 agonist that promotes anti-tumor immunity by remodeling the TME and activating DCs and that may provide a new way to overcome resistance to current anti-tumor immunotherapy in colorectal cancer.

Glioblastoma, the most common and aggressive primary brain tumor, remains a significant challenge in oncology due to its immunosuppressive tumor microenvironment (TME). This review summarizes the complex interplay of immune cells and cytokines within the TME, which contribute to immune evasion and tumor progression. We further emphasize the synergistic crosstalk among these components and how it shapes therapeutic vulnerability. Besides, we highlight recent advancements in immunotherapy, including immune checkpoint inhibitors, CAR-T cell therapy, NK cell therapy, oncolytic viruses, and vaccine-based strategies. Despite promising preclinical and clinical results, overcoming the immunosuppressive TME remains a critical hurdle. This review underscores the potential of targeting the TME to enhance therapeutic outcomes in glioblastoma.

Cancer is the most common malignancy, with over 2 million new cases and nearly 1.8 million deaths worldwide annually. Non-small-cell lung cancer (NSCLC) is the predominant subtype, accounting for the majority of cases. Myeloid-derived suppressor cells (MDSCs), which originate from monocytes and typically differentiate into macrophages and granulocytes, possess potent immunosuppressive capabilities. MDSCs regulate immune responses in various pathological conditions and are strongly associated with poor prognosis in cancer patients. This study aims to elucidate the complex interplay between MDSCs, immune cells, and tumours in the NSCLC tumour microenvironment (TME). By integrating single-cell RNA sequencing (scRNA-seq) data with bulk RNA sequencing (Bulk RNA-seq) data, we identified MDSCs as the target cell population and used Monocle software (v2.22.0) to infer their developmental trajectories. We identified key genes associated with MDSCs differentiation processes and classified MDSCs into seven distinct states based on their functional roles. Furthermore, we constructed a prognostic risk model based on the impact of MDSCs differentiation on NSCLC prognosis, utilizing Elastic Net regression and multivariate Cox regression analysis of Bulk RNA-seq data. The model's performance and accuracy were validated using both internal and external validation sets. Additionally, we compared risk scores with clinical pathological features and the relationship between risk scores and key immune cells in the immune microenvironment, demonstrating the model's clinical predictive value. We also explored how prognostic genes contribute to poor prognosis in NSCLC. Moreover, small molecule compounds targeting these prognostic genes were screened, and their anti-tumour effects were evaluated as potential therapeutic strategies for NSCLC treatment. This study not only reveals the complex regulatory mechanisms of MDSCs in the NSCLC immune microenvironment but also successfully constructs a prognostic risk model based on MDSCs differentiation states. The model demonstrates excellent clinical performance in predicting patient prognosis, effectively identifying high-risk patients and providing robust support for individualized treatment and immunotherapy decisions. Through association analyses with key immune cells in the immune microenvironment and clinical pathological features, our model can assist clinicians in formulating more precise treatment plans based on patients' immune status and tumour characteristics. Furthermore, we identified small molecule compounds targeting these prognostic genes, providing novel and promising therapeutic targets for NSCLC, which could further enhance treatment efficacy and improve patients' survival quality.

This study aimed to examine the bilateral stability of the tear film in patients with unilateral neurotrophic keratitis and to observe changes in corneal nerve and immune cells under confocal microscopy.

A prospective cross-sectional study included 63 patients with confirmed neurotrophic keratitis (NK) and 40 normal controls of similar sex and age. NK patients were divided into stage 1 and stage 2 based on the severity of the disease. Tear meniscus height (TMH), first non-invasive tear film break-up time (NIBUT-f), and corneal fluorescein staining were assessed. Corneal sensitivity was assessed using a Cochet-Bonnet esthesiometer. The corneal subbasal nerve plexus (SNP) and dendritic cells (DCs) were imaged using in vivo confocal microscopy (IVCM), and the SNP was analyzed using the fully automated corneal nerve analysis software "ACCmetric."

Eyes with NK stage 2 showed worse performance in TMH, NIBUT-f, corneal fluorescein staining score, corneal sensitivity examination, SNP parameters, and DC density compared to NK stage 1 (all p < 0.001). The contralateral eyes of NK patients had significantly shorter NIBUT-f and higher dendritic cell density than controls (p < 0.001).

The contralateral eyes of NK patients are more prone to dry eye signs than those of normal subjects and should be monitored and treated promptly. Increased dendritic cell numbers in the contralateral eyes of NK patients suggest bilateral immune alterations in unilateral disease.

Vaccines usually contain an adjuvant that activates innate immunity to promote the acquisition of adaptive immunity. Aluminum and lipid nanoparticles have been used for this purpose, but their accumulation or widespread circulation in the body can lead to adverse effects. In contrast, physical adjuvants, which use physical energy to transiently stress tissues, do not persist in exposed tissues or cause lasting adverse effects. Herein, we investigate the effects of intradermal injection of endotoxin-free ovalbumin (OVA) protein alone without additional adjuvants using a needle-free pyro-drive jet injector (PJI) on tumor vaccination efficacy. Intradermal injection of OVA protein alone using PJI significantly increased OVA-specific CD8+ T cell expansion in the lymph node, although lymph node swelling was much less than when aluminum hydroxide was used. The injection also induced OVA-specific killing activity and antibody production and showed strong CD8+ T cell-dependent prophylactic antitumor effects against transplanted E.G7-OVA tumors. In particular, intradermal injection of the fluorescent OVA protein significantly enhanced its uptake by XCR1+ dendritic cells, which have a strong ability to cross-present extracellular proteins in the skin and draining lymph nodes. In addition, the injection increased the expression of HMGB1, one of the potent danger signals whose expression has been reported to increase in response to shear stress. Thus, intradermal injection of OVA protein alone without any additional adjuvants using PJI induces potent CD8+ T cell-mediated antitumor immunity by enhancing its uptake into XCR1+ dendritic cells, which have a high cross-presentation capacity accompanied by an increased expression of shear stress-induced HMGB1.

Dendritic cell-based therapeutic tumor vaccines are an active immunotherapy that has been commonly tried in the clinic,traditional treatment modalities for malignant tumors, such as surgery, radiotherapy and chemotherapy, have the disadvantages of high recurrence rates and side effects. The dendritic cell vaccination destroys cells from tumors by means of the patient's own system of immunity, a very promising treatment. However, due to the suppression of the tumor immune microenvironment, the difficulty of screening for optimal specific antigens, and the high technical difficulty of vaccine production. Most tumor vaccines currently available in the clinic have failed to produce significant clinical therapeutic effects. In this review, the fundamentals of therapeutic dendritic cells vaccine therapy are briefly outlined, with a focus on the progress of therapeutic Dendritic cells vaccine research in the clinic and the initiatives undertaken to enhance dendritic cell vaccinations' anti-tumor effectiveness. It is believed that through the continuous exploration of novel therapeutic strategies, therapeutic dendritic cells vaccines can play a greater role in improving tumor treatment for tumor patients.

Since the beginning of the COVID-19 pandemic, the development of messenger RNA (mRNA) vaccines has made significant progress in the pharmaceutical industry. The two COVID-19 mRNA vaccines from Moderna and Pfizer/BioNTech have been approved for marketing and have made significant contributions to preventing the spread of SARS-CoV-2. In addition, mRNA therapy has brought hope to some diseases that do not have specific treatment methods or are difficult to treat, such as the Zika virus and influenza virus infections, as well as the prevention and treatment of tumors. With the rapid development of in vitro transcription (IVT) technology, delivery systems, and adjuvants, mRNA therapy has also been applied to hereditary diseases such as Fabry's disease. This article reviews the recent development of mRNA vaccines for structural modification, treatment and prevention of different diseases; delivery carriers and adjuvants; and routes of administration to promote the clinical application of mRNA therapies.

Tuberculosis (TB) is a disease of major public health concern with an estimated one-fourth of the world currently infected with M. tuberculosis (Mtb) bacilli. Mtb infection occurs after inhalation of Mtb, following which, highly structured immune structures called granulomas form within lungs to immunologically restrain and physically constrain spread of infection. Most lung granulomas are successful at controlling or even eliminating their bacterial loads, but others fail to control infection and promote disease. Granulomas also form within lung-draining lymph nodes (LNs), variably affecting immune function. Both lung and LN granulomas vary widely in ability to control infection, even within a single host, with outcomes ranging from bacterial clearance to uncontrolled bacterial growth. While lung granulomas are well-studied, data on LN granulomas are scarce; it is unknown what mechanisms drive LN Mtb infection progression and variability in severity. Recent data suggest that LN granulomas are niches for bacterial replication and can reduce control over lung infection. To identify mechanisms driving LN Mtb infection, we developed a multi-scale compartmental model that includes multiple lung-draining LNs, blood. We calibrated to data from a nonhuman primate TB model (one of the only models that parallels human TB infection). Our model predicts temporal trajectories for LN macrophage, T-cell, and Mtb populations during simulated Mtb infection. We also predict a clinically measurable infection feature from PET/CT imaging, FDG avidity. Using uncertainty and sensitivity analysis methods, we identify key mechanisms driving LN granuloma fate, T-cell efflux rates from LNs, and a role for LNs in pulmonary infection control.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell and plasma cell malignancies, and numerous promising targets against solid tumours are being explored. Despite their initial therapeutic success in hematological cancers, relapse occurs in a significant fraction of patients, highlighting the need for further innovations in advancing CAR T cell therapy. Tumour antigen heterogeneity and acquired tumour resistance leading to antigen escape (antigen loss/downregulation) have emerged as a crucial factor contributing to immune escape and CAR T cell resistance, particularly in the case of solid tumours with only limited success achieved to date. In this review, we discuss mechanisms of tumour relapse in CAR T cell therapy and the promising strategies that are under development to overcome multiple resistance mechanisms, thereby reducing outgrowth of antigen escape variants. Specifically, we emphasize the importance of designing clinical translational strategies to enhance CAR T cell crosstalk with host immune cells, eliciting endogenous antitumour immune responses through antigen/epitope spreading, which offers a genuine solution to the limitations of targeting tumour antigen heterogeneity in solid tumours with monospecific T cell therapies.

Mapping enhancers and target genes in disease-related cell types provides critical insights into the functional mechanisms of genome-wide association studies (GWAS) variants. Single-cell multimodal data, which measure gene expression and chromatin accessibility in the same cells, enable the cell-type-specific inference of enhancer-gene pairs. However, this task is challenged by high data sparsity, sequencing depth variation, and the computational burden of analyzing a large number of pairs. We introduce scMultiMap, a statistical method that infers enhancer-gene association from sparse multimodal counts using a joint latent-variable model. It adjusts for technical confounding, permits fast moment-based estimation and provides analytically derived p-values. In blood and brain data, scMultiMap shows appropriate type I error control, high statistical power, and computational efficiency (1% of existing methods). When applied to Alzheimer's disease (AD) data, scMultiMap gives the highest heritability enrichment in microglia and reveals insights into the regulatory mechanisms of AD GWAS variants.

This Part 2 of a bipartite review commences with the delineation of a conceptual model outlining the fundamental role of injury-induced regulated cell death (RCD) in the release of DAMPs that drive innate immune responses involved in early inflammation-related allograft dysfunction and alloimmune-mediated allograft rejection. In relation to this topic, the focus is on the divergent role of donor and recipient dendritic cells (DCs), which become immunogenic in the presence of DAMPs to regulate alloimmunity, but in the absence of DAMPs acquire tolerogenic properties to promote allotolerance. With respect to this scenario, proposals are then made for leveraging RCD and DAMPs as biomarkers during normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) of transplant organs from DCD donors, a strategy poised to significantly enhance current policies for assessing donor organ quality. The focus is then on the ambitious goal to target RCD and DAMPs therapeutically during NRP and NMP, aiming to profoundly suppress subsequently early allograft inflammation and alloimmunity in the recipient. This strategic approach seeks to prevent the activation of intragraft innate immune cells including DCs during donor organ reperfusion in the recipient, which is driven by ischemia/reperfusion injury-induced DAMPs. In this context, available inhibitors of various types of RCD, as well as scavengers and inhibitors of DAMPs are highlighted for their promising therapeutic potential in NRP and NMP settings, building on their proven efficacy in other experimental disease models. If successful, this kind of therapeutic intervention should also be considered for application to organs from DBD donors. Finally, drawing on current global insights into the critical role of RCD and DAMPs in driving innate inflammatory and (allo)immune responses, targeting their inhibition and/or prevention during normothermic perfusion of transplant organs from DCD donors - and potentially DBD donors - holds the transformative potential to not only alleviate transplant dysfunction and suppress allograft rejection but also foster allograft tolerance.

Vaccinology has revolutionized modern medicine, delivering groundbreaking solutions to prevent and control infectious diseases while pioneering innovative strategies to tackle non-infectious challenges, including cancer. Traditional vaccines faced inherent limitations, driving the evolution of next-generation vaccines such as subunit vaccines, peptide-based vaccines, and nucleic acid-based platforms. Among these, nucleic acid-based vaccines, including DNA and mRNA technologies, represent a major innovation. Pioneering studies in the 1990s demonstrated their ability to elicit immune responses by encoding specific antigens. Recent advancements in delivery systems and molecular engineering have overcome initial challenges, enabling their rapid development and clinical success. This review explores nucleic acid-based vaccines, including chemically modified variants, by examining their mechanisms, structural features, and therapeutic potential, while underscoring their pivotal role in modern immunization strategies and expanding applications across contemporary medicine.

Using Tetrahedral framework nucleic acids, we combined antigenic peptides to create the "DART" vaccine: DNA framework-Antigenic peptide-RNA modification-Targeting aptamer coupling. Generating antigen-specific tolerogenic dendritic cells (tolDCs), for systemic lupus erythematosus (SLE) is a potential therapeutic strategy for addressing compromised autoimmune tolerance. However, simple antigenic peptides degrade easily, lack specificity for delivery to dendritic cells (DCs), and cannot transform DCs to tolDCs. Therefore, this study aims to employ DART to generate tolDCs and compare DART-treated DCs to tolDCs. DART improved peptide stability, specifically targeted DCs, induced tolDCs in situ, and showed promising outcomes in mitigating SLE symptoms in the MRL/lpr mouse model. DART effectively normalized the plasma cytokine levels, glomerulonephritis, and joint lesions in MRL/lpr mice. These findings highlight the potential of the DART vaccine to induce transformation of DCs to tolDCs and address SLE symptoms, suggesting novel therapeutic utility. These findings may advance vaccine design for various autoimmune diseases.

Dendritic cells (DCs) are versatile professional antigen-presenting cells and play an instrumental role in the generation of antigen-specific T-cell responses. Modulation of DC function holds promise as an effective strategy to improve anti-tumor immunotherapy efficacy and enhance self-antigen tolerance in autoimmune diseases.

Wild-type (WT) and TLR2 knockout (KO) mice at 2 weeks of age were injected intraperitoneally (i.p.) with a single dose of diethylnitrosamine (DEN) to induce hepatocellular carcinoma (HCC). Four weeks later, WT and KO mice were randomly divided into control and treatment groups and treated once every two days for 30 weeks with phosphate buffered saline (PBS) and a mix of 4 TLR2-activating lactic acid-producing probiotics (LAP), respectively. Mice were euthanized after 30 weeks of LAP treatment and their liver tissues were collected for gene expression, histological, flow cytometric and single-cell RNA sequencing analyses.

We demonstrate here that oral administration of a mix of TLR2-activating LAP triggers a marked accumulation of regulatory DCs (rDCs) in the liver of mice. LAP-treated mice are protected from DEN-induced liver injury, fibrosis and HCC in a TLR2-dependent manner. Single-cell transcriptome profiling revealed that LAP treatment determines an immunosuppressive hepatic T-cell program that is characterized by a significantly reduced cytotoxic activity. The observed functional changes of T cells correlated well with the presence of a hepatic DC subset displaying a regulatory or tolerogenic transcriptional signature.

Overall, these data suggest that stimulation of regulatory dendritic cells (rDCs) in the liver by LAP suppresses cytotoxic T-cell function and alleviates DEN-induced liver damage, fibrosis and tumorigenesis.

Aging is associated with immune senescence and gut dysbiosis, both of which are heavily influenced by the diet. In this review, we summarize current knowledge regarding the impact of diets high in fiber, protein, or fat, as well as different dietary components (tryptophan, omega-3 fatty acids, and galacto-oligosaccharides) on the immune system and the gut microbiome in aging. Additionally, this review discusses how aging alters tryptophan metabolism, contributing to changes in immune function and the gut microbiome. Understanding the relationship between diet, the gut microbiome, and immune function in the context of aging is critical to formulate sound dietary recommendations for older individuals, and these personalized nutritional practices will ultimately improve the health and longevity of the elderly.

Over the past few decades, there has been significant advancement in the field of tumor immunotherapy. For many years vaccination against infectious diseases have been available. On the other hand very few cancer vaccines have been approved for human use. Ideal Cancer vaccines are biological response modifier work by stimulating both humoral and cellular immunity while overcoming the immunological suppression found in tumor. Two types of cancer vaccine: Prophylactic and therapeutic cancer vaccines are recommended for clinical use of individuals. HPV and HBV vaccines are the two widely used preventive vaccine used for treatment of cervical and hepatocellular carcinoma respectively and are approved by Food and Drug Administration (FDA). In therapeutic vaccine only three are approved: Sipuleucel T-cell vaccine for treatment refractory prostatic cancer, BCG vaccine for early bladder cancer and T-VEC for inoperable melanoma. Active ingredient in all cancer vaccines is an antigen. Antigens used for formulating cancer vaccines along with adjuvants optimizes immunogenicity in it. Heterogeneity within and between cancer types, screening and identifying suitable antigen specific to tumors and selection of vaccine delivery platforms are challenges in the development of vaccines. Adoptive cell therapy, Chimeric antigen receptor T cell therapy are recent breakthrough for cancer treatment.

Vibrio cholerae cytolysin (VCC) is a potent exotoxin secreted by Vibrio cholerae, the etiological agent of the severe diarrheal disease cholera. VCC is a membrane-damaging pore-forming toxin by nature, and is well known for its ability to cause host cell death. Using wild type V. cholerae and VCC-deleted mutant variant of the bacteria, we show that VCC plays an important role in the inflammatory responses during infection in mice. This observation supports that VCC can function as a pathogen-associated molecular pattern (PAMP). Toll-like receptors (TLRs) are the key initiators of inflammation. Upon ligand recognition, TLR1 and TLR6 generally form heterodimers with TLR2 for triggering pro-inflammatory signals. In the present study, we show that VCC engages novel TLR1/4 heterodimer assembly, and elicits pro-inflammatory responses in both dendritic cells (DCs) and macrophages. Along with TLR1/4, VCC-induced pro-inflammatory response in macrophages also involves TLR2. It has been shown earlier that VCC is implicated in the V. cholerae-mediated killing of the immune cells following biofilm formation. Here we show that TLRs play an important role in VCC-mediated killing of DCs and macrophages following V. cholerae infection. Interestingly, we find that TLR1/4 signalling is specifically crucial for the VCC-induced inflammatory and death responses in DCs, as well as in mice. Additionally, we observe that similar to DCs and macrophages, TLR1/4-MyD88 play an important role in VCC-mediated inflammatory responses in another crucial immune cell type, neutrophils. Taken together, our study shows novel TLR heterodimer formation, differential recognition of the same ligand by different TLR combination in cell type-dependent manner, and their implications in the context of V. cholerae and VCC-induced immune cell death and mortality.

Cancer nanovaccines hold the promise for personalization, precision, and pliability by integrating all the elements essential for effective immune stimulation. An effective immune response requires communication and interplay between antigen-presenting cells (APCs), tumor cells, and immune cells to stimulate, extend, and differentiate antigen-specific and non-specific anti-tumor immune cells. The versatility of nanomedicine can be adapted to deliver both immunoadjuvant payloads and antigens from the key players in immunity (i.e., APCs and tumor cells). The imperative for novel cancer medicine is particularly pressing for less common but more devastating KIT-mutated acral and mucosal melanomas that are resistant to small molecule c-kit and immune checkpoint inhibitors. To overcome this challenge, we successfully engineered nanotechnology-enabled hybrid biomimetic nanovaccine (HBNV) comprised of membrane proteins (antigens to activate immunity and homing/targeting ligand to tumor microenvironment (TME) and lymphoid organs) from fused cells (of APCs and tumor cells) and immunoadjuvant. These HBNVs are efficiently internalized to the target cells, assisted in the maturation of APCs via antigens and adjuvant, activated the release of anti-tumor cytokines/inhibited the release of immunosuppressive cytokine, showed a homotypic effect on TME and lymph nodes, activated the anti-tumor immune cells/downregulated the immunosuppressive immune cells, reprogram the tumor microenvironment, and showed successful anti-tumor therapeutic and prophylactic effects.

Pancreatic cancer is an aggressive tumor with high metastatic potential which leads to decreased survival rate and resistance to chemotherapy and immunotherapy. Nearly 90% of pancreatic cancer comprises pancreatic ductal adenocarcinoma (PDAC). About 80% of diagnoses takes place at the advanced metastatic stage when it is unresectable, which renders chemotherapy regimens ineffective. There is also a dearth of specific biomarkers for early-stage detection. Advances in next generation sequencing and single cell profiling have identified molecular alterations and signatures that play a role in PDAC progression and subtype plasticity. Most chemotherapy regimens have shown only modest survival benefits, and therefore, translational approaches for immunotherapies and combination therapies are urgently required. In this review, we have examined the immunosuppressive and dense stromal network of tumor immune microenvironment with various metabolic and transcriptional changes that underlie the pro-tumorigenic properties in PDAC in terms of phenotypic heterogeneity, plasticity and subtype co-existence. Moreover, the stromal heterogeneity as well as genetic and epigenetic changes that impact PDAC development is discussed. We also review the PDAC interaction with sequestered cellular and humoral components present in the tumor immune microenvironment that modify the outcome of chemotherapy and radiation therapy. Finally, we discuss different therapeutic interventions targeting the tumor immune microenvironment aimed at better prognosis and improved survival in PDAC.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by T cell-mediated pancreatic β cell destruction. To evaluate the effects of metformin on immune cells in autoimmune diabetes, we administered metformin intraperitoneally to two T1D mouse models and analyzed autoimmune diabetes progression. In a cyclophosphamide (CY)-induced T1D model in male non-obese diabetic (NOD) mice, intraperitoneal administration of metformin significantly prevented autoimmune diabetes. Treatment with metformin showed a decrease in activated T cells, CD44hiCD62Llo effector memory cells, macrophages, and dendritic cells (DCs), and an increase in CD44hiCD62Lhi central memory cells, B cells, and regulatory T cells (Tregs) in splenocytes. Interestingly, metformin treatment showed a decrease in activated T cells, CD4+ effector memory T cells and Th1-type antigen-specific cells in PLN cells. IL-17 production was significantly suppressed in metformin-treated mice. TNF-α production from DCs in vitro was dose-dependently suppressed by metformin. Activity of mTOR signaling was significantly reduced in CD4+ T cells, CD8+ T cells, and B220+ B cells. In addition, activities of mTOR and STAT3 signaling in DCs were also reduced significantly. Furthermore, metformin treatment in female NOD mice, a spontaneous T1D model, significantly suppressed autoimmune diabetes onset as well and an increase in Tregs was observed. Our results suggest that metformin may suppress autoimmunity and have therapeutic potential in T1D progression as an immunomodulator.

Although several traditional Chinese medicine formulas have demonstrated remarkable outcomes in suppressing the severe gastrointestinal toxicity induced by irinotecan (CPT-11), few studies have investigated whether enhanced anti-cancer efficacy and reduced intestinal toxicity can be achieved through co-administration. CPT-11, as a first-line drug for treating colorectal cancer, has the side effect of intestinal toxicity. Previous studies have primarily focused on using traditional Chinese medicine to alleviate diarrhea caused by CPT-11. The combination of the classic Chinese medicine prescription Gegen Qinlian decoction (GQD) extract and CPT-11 can significantly reduce its intestinal toxicity. However, the mechanism by which it enhances anti-cancer effects remains to be elucidated.

To investigate the combined effects of GQD and CPT-11 on colorectal cancer progression and intestinal toxicity.

The CT-26 xenograft tumor-bearing mouse model was established to evaluate the synergistic antitumor effects of GQD extract and CPT-11. Tumor size and tumor tissue changes were assessed, and flow cytometry was employed to analyze immune cell populations, thereby evaluating the impact of the combined treatment on tumor growth inhibition and immune modulation. Under anaerobic glycolysis conditions, glucose uptake and cell viability of CT26 cells were measured, and Western blotting analysis was used to determine the protein expression of PKM2 and GAPDH in tumors, assessing the metabolic impact of GQD extract on cancer cells. Flow cytometry was also used to assess the polarization of macrophages in colon tissue, and ELISA was employed to measure cytokine levels in colon tissue, evaluating the protective effect of GQD extract on the colon.

The combination of GQD extract and CPT-11 significantly increased tumor growth suppression and decreased intestinal toxicity in the mouse model. The anti-cancer synergy was reduced Treg cell immunosuppression and increased CD4+ and CD8+ T cell populations. GQD extract regulated glucose uptake and cell viability in CT-26 cells under anaerobic glycolysis, potentially disrupting cancer cell glycolysis. GQD also alleviated intestinal toxicity by modulating cytokine levels and promoting macrophage polarization from M1 to M2 in colon tissues.

The study indicates that GQD extract improves CPT-11 efficacy in treating colorectal cancer and provides insights into the synergistic effects of TCM formulas in cancer treatment.

Strategies to improve the therapeutic efficacy of cancer immunotherapy with immune checkpoint inhibitors include targeting additional immunosuppressive compartments in the tumor microenvironment (TME). Inhibitory macrophages (Mφ) can be one of the most abundant immune cells in the TME associated with poor prognosis. However, to date, selective Mφ depletion strategies as a cancer immunotherapy have not been successful in clinical trials. Macrophage Receptor with Collagenous Structure (MARCO) is one of a family of class-A scavenger receptors expressed by Mφ in the TME and is one of the most upregulated transcripts in dendritic cells (DC) following their ex vivo uptake of dead tumor cells. The clinical significance of MARCO expression in the TME is not fully understood.

The therapeutic potential of targeting MARCO by an anti-murine MARCO (ED31, clone ED31) monoclonal antibody, which inhibits ligand-binding to MARCO, was explored in combination with anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) or anti-programmed cell death protein-1 (anti-PD-1) in C57BL/6J mice bearing B16F10 or Pan02 tumors. The mechanism by which ED31 impacts the TME was investigated by flow cytometry in the different treatment arms. The contribution of Mφ was assessed by both in vivo depletion and in vitro functional assays. Chemokine production was measured by a bead-based multiplex assay.

ED31 enhanced antitumor efficacy of anti-CTLA-4, but not of anti-PD-1. Analysis of the TME revealed that adding ED31 to anti-CTLA-4 substantially increased immune cell infiltration, including mature conventional DC recruitment, that was due to a switch to M1-pattern chemokines by Mφ. Mφ depletion completely abrogated both the increase in immune cell infiltration and chemokine production, and abolished the antitumor efficacy of the combination therapy.

Targeting MARCO as an additional checkpoint in the TME can offer a strategy to improve the antitumor efficacy of anti-CTLA-4 through a mechanism involving Mφ reprogramming rather than their depletion.

With the use of T cell receptor T cells (TCR-T cells) and chimeric antigen receptor T cells (CAR-T cells), T-cell immunotherapy for cancer has advanced significantly in recent years. CAR-T cell therapy has demonstrated extraordinary success when used to treat hematologic malignancies. Nevertheless, there are several barriers that prevent this achievement from being applied to solid tumors, such as challenges with tumor targeting and inadequate transit and adaption of genetically modified T-cells, especially in unfavorable tumor microenvironments The deficiencies of CAR-T cell therapy in the treatment of solid tumors are compensated for by TCR-T cells, which have a stronger homing ability to initiate intracellular commands, 90% of the proteins can be used as developmental targets, and they can recognize target antigens more broadly. As a result, TCR-T cells may be more effective in treating solid tumors. In this review, we discussed the structure of TCR-T and have outlined the drawbacks of TCR-T in cancer therapy, and suggested potential remedies. This review is crucial in understanding the current state and future potential of TCR-T cell therapy. We emphasize how important it is to use combinatorial approaches, combining new combinations of various emerging strategies with over-the-counter therapies designed for TCR-T, to increase the anti-tumor efficacy of TCR-T inside the TME and maximize treatment safety, especially when it comes to solid tumor immunotherapies.

Renal tumors with inferior vena cava tumor thrombus (IVCTT) remain a challenge in urology. However, in vivo models remain unavailable, which hampers the elucidation of its pathogenesis, identification of therapeutic targets, and screening for effective drugs. In this study, we initially develop two IVCTT models in BALB/c and BALB/c-nu/nu mice using the mouse Renca cell line. The pathological features and immune microenvironment of IVCTT in immunocompetent mice closely resembles those observed in humans. Single-cell transcriptome sequencing, immunohistochemistry and multiplex immunohistochemistry reveal a predominance of monocytes, macrophages, and neutrophils within IVCTT, mirroring the cellular composition of the human IVCTT; however, fewer lymphocytes are observed. The IVCTT in immunodeficient mice progresses much faster than in immunocompetent mice. More importantly, we successfully use the human tumor cell line on the BALB/c nu/nu mice to create an IVCTT model. The proposed in vivo models mimic the progression of renal tumors with IVCTT, clarify that the immune system can inhibit tumor thrombus progression, and provide tools for subsequent mechanistic research and translational preclinical studies.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

The perioperative period is crucial for determining postoperative tumor recurrence and metastasis. Various factors in postoperative lesions can diminish the therapeutic effect of conventional chemoradiotherapy, while emerging immunotherapy is restricted. The combination use of inflammatory inhibitors during treatment is also controversial. Here, a modular microneedle prepared from engineered keratin proteins is reported, which spatially and temporally differentiates the microenvironment of immune cell activation required for immunotherapy from that of wound healing. The recombinant keratin-84-T-based needle root layer, mainly retained in the epidermis, facilitated dendritic cell recruitment to achieve maximum antigen presentation of loaded vaccines. Meanwhile, the recombinant keratin-81-1Aα-based needle tip layer, located within the dermis, rapidly mitigated inflammatory responses while promoting tissue repair and regeneration. Unlike simply mixing immunotherapy and wound treatment, this spatiotemporal segmentation approach maximized the efficacy of immune therapeutics while promoting wound healing, making it suitable for application throughout the perioperative period.

Non-tuberculous Mycobacteria (NTM) are found extensively in various environments, yet most are non-pathogenic. Only a limited number of these organisms can cause various infections, including those affecting the lungs, skin, and central nervous system, particularly when the host's autoimmune function is compromised. Among these, Non-tuberculous Mycobacteria Pulmonary Diseases (NTM-PD) are the most prevalent. Currently, there is a lack of effective treatments and preventive measures for NTM infections. This article aims to deepen the comprehension of the pathogenic mechanisms linked to NTM and to formulate new intervention strategies by synthesizing current research and detailing the different tactics used by NTM to avoid elimination by the host's immune response. These intricate mechanisms not only affect the innate immune response but also successfully oppose the adaptive immune response, establishing persistent infections within the host. This includes effects on the functions of macrophages, neutrophils, dendritic cells, and T lymphocytes, as well as modulation of cytokine production. The article particularly emphasizes the survival strategies of NTM within macrophages, such as inhibiting phagosome maturation and acidification, resisting intracellular killing mechanisms, and interfering with autophagy and cell death pathways. This review aims to deepen the understanding of NTM's immune evasion mechanisms, thereby facilitating efforts to inhibit its proliferation and spread within the host, ultimately providing new methods and strategies for NTM-related treatments.

Plasmacytoid dendritic cells produce large amounts of type-I interferon (IFN-I) upon sensing nucleic acid components of pathogens by Toll-like receptors (TLR7 and TLR9). The transcription factor Spi-B has the DNA-binding Ets domain, and transactivates the Ifna4 promoter co-operatively with IFN regulatory factor-7 (IRF-7) for TLR7/TLR9-induced IFN-I production. Spi-B associates with IRF-7, and activates transcription by binding to the 5'-AGAA-3' sequence, being different from 5'-GGAA-3', known as the Ets domain recognition sequence. To understand the molecular mechanism for the co-operative transactivation of the Ifna4 promoter by Spi-B and IRF-7, we performed X-ray structural determination of the Spi-B Ets domain in complex with target DNAs, including 5'-AGAA-3' and 5'-GGAA-3' sequences. Furthermore, we conducted a modeling study of the complex of the Spi-B and IRF-7 with Ifna4 promoter DNA. X-ray structures showed that the binding of the Spi-B Ets domain induces a kink in DNA at the recognition sequence, and a more kinked DNA structure was observed in 5'-AGAA-3' than 5'-GGAA-3'. A modeling study showed that the Spi-B-induced kinked DNA structure in 5'-AGAA-3' is favorable for Spi-B and IRF-7 to approach each other for association on DNA.

Cancer vaccines are promising therapeutic approaches to enhance specific T-cell immunity against most solid tumors. By stimulating anti-tumor immunity, clearing minimal residual disease, and minimizing adverse effects, these vaccines target tumor cells and are effective when combined with immune checkpoint blockade or other immunotherapies. However, the development of tumor cell-based vaccines faces quality issues due to poor immunogenicity, tumor heterogeneity, a suppressive tumor immune microenvironment, and ineffective delivery methods. In contrast, extracellular vesicles (EVs), naturally released by cells, are considered the ideal drug carriers and vaccine platforms. EVs offer highly organ-specific targeting, induce broader and more effective immune responses, and demonstrate superior tissue delivery ability. The development of EV vaccines is crucial for advancing cancer immunotherapy. Compared to cell-based vaccines, EV vaccines produced under Good Manufacturing Practices (GMP) offer advantages such as high safety, ease of preservation and transport, and a wide range of sources. This review summarizes the latest research findings on EV vaccine and potential applications in this field. It also highlights novel neoantigens for the development of EV vaccines against cancer.

This study assesses the associations between dendritic cells, HPV 6 and 11, and Recurrent Respiratory Papillomatosis (RRP) aggressiveness.

The Derkay score was calculated using information obtained from the medical records. Biopsies from 36 patients with juvenile RRP (JRRP) and 43 adult RRP (ARRP) patients were analyzed under light microscopy, and their clinical data were collected. Immunohistochemical analysis using antibodies against CD83, CD1a, Factor XIIIa, and S100 was performed, and inflammatory cells were quantified. Data obtained were analyzed using the chi-squared test, in addition to the Mann-Whitney and Z tests for two proportions, considering a confidence interval of 95% and p < 0.05 as statistically significant.

A higher quantity of S100 was identified in the epithelium (p < 0.001) and in the conjunctive tissue (p = 0.027) among the ARRP cases, while CD83 (p = 0.025) and Factor XIIIa (p = 0.018), both in the epithelium, were identified among the JRRP cases. We observed significant association between a higher quantity of CD83 in the epithelium in the juvenile group with a low Derkay index (p = 0.034) and with HPV 6 (p = 0.039).

An increased quantity of dendritic cells is present in individuals diagnosed with RRP, regardless of age, and this may be related to the lower Derkay index, regardless of the HPV type detected.