Search Results (863)

Natural killer (NK) cells are central to antiviral immunity through a balance of activating and inhibitory receptors, including killer immunoglobulin-like receptors (KIRs). We have previously observed that an increased frequency of the inhibitory receptor KIR2DL2 and its ligand HLA-C1 is associated with heightened susceptibility to human herpesvirus (HHV) infection, supporting a role for KIR-mediated NK cell regulation in host–virus interactions. We investigated whether the co-infection of SARS-CoV-2 and human herpesvirus 6 (HHV-6) might be connected to the expression of KIR2DL2/HLA-C1. We analyzed 110 SARS-CoV-2-positive subjects and 109 SARS-CoV-2-negative subjects for the KIR2DL2 and HLA-C1 genotype and for HHV-6A/B reactivation in plasma samples. SARS-CoV-2-positive subjects showed a significantly higher frequency of the KIR2DL2/HLA-C1 haplotype and increased reactivation of HHV-6A. Among deceased and comorbid patients, the co-occurrence of the KIR2DL2/HLA-C1 haplotype and HHV-6A DNAemia was more frequent, particularly in those with cardiovascular disorders. These findings suggest that the KIR2DL2/HLA-C1 haplotype might promote NK cell inhibition, facilitating HHV-6A persistence and contributing to immune dysregulation during SARS-CoV-2 infection. The combined presence of KIR2DL2/HLA-C1 and HHV-6A may, therefore, represent a molecular signature of COVID-19 outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and many patients cannot undergo curative surgery due to frailty. Multimodal prehabilitation: combining exercise, nutrition, and psychological support improves functional readiness, but its biological impact on the PDAC tumor microenvironment (TME) is unclear. In this exploratory pilot study, we profiled resected PDAC tissues from prehabilitation-treated patients and matched controls using NanoString GeoMx Digital Spatial Profiling across immune, tumor, and stromal compartments (n = 4). Transcriptomic signatures were analyzed via differential expression, pathway enrichment, and MCP-counter deconvolution; protein-level validation used multiplex immunofluorescence (n = 8). Ligand–receptor modeling assessed cell–cell communication, and prognostic relevance was evaluated in TCGA-PDAC (n = 178). Prehabilitation was associated with increased NK-cell cytotoxicity, interferon response, and chemokine recruitment, as well as higher neutrophil signatures (p < 0.01) and reduced fibroblast signatures (p < 0.05). Tumor regions showed lower MAPK and PI3K/AKT activity, while stroma exhibited decreased TGF-β and Wnt signaling. Immunofluorescence confirmed neutrophil infiltration and reduced fibroblast density. TCGA analysis linked neutrophil-high/fibroblast-low profiles to longer survival (1044.6 vs. 458.7 days, p = 0.0052). These findings suggest prehabilitation may promote a more immune-active, less fibrotic TME in PDAC, resembling transcriptional states associated with improved survival. Prospective studies integrating biological and clinical endpoints are warranted. Full article

Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody–drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need. Full article

Background: Axillary lymph node (ALN) metastasis is a critical prognostic determinant in breast cancer (BC) that informs surgical management. However, surgically clearing the axilla carries morbidity, so less invasive methods of risk-stratifying patients are needed. ALN fine needle aspiration (FNA) is currently used to detect BC metastases, but these samples also contain immune cells. Methods: Cells obtained via FNA from BC-patient-derived ALNs were analysed using flow cytometry. Results: FNA acquires sufficient leukocytes for comprehensive immunophenotyping of reactive, patient-derived ALNs. All CD4⁺ and CD8⁺ T-cell subsets (naïve, terminal effector, central memory, and effector memory) and rarer (<2%) natural killer (NK) and plasmacytoid dendritic cell (pDC) populations are represented. Importantly, the immune-cell profile of one reactive ALN appears to reflect the immune status of the patient’s axilla. Furthermore, FNA captures immune differences between patients with ≤1 or ≥2 metastatic ALNs. Increased numbers of naïve CD4⁺ T cells, but fewer terminal effector, central memory, and effector memory subpopulations, were obtained from patients with ≥2 metastatic ALNs. Moreover, despite their sparse distribution pattern on whole-section immunohistochemistry (WSI), FNA revealed that CD56⁺ NK cell activation receptors were decreased in patients with ≥2 metastatic ALNs. Finally, FNA captured a decrease in pDCs in patients with ≤1 metastatic ALNs, despite their clustered distribution pattern on WSI. Conclusions: FNA is not only feasible for sampling leukocytes from reactive, patient-derived ALNs, but also identifies immune-cell profiles that reflect axillary tumour burden in BC. Thus, this technique could be used to risk-stratify BC patients in the future. Full article

Lidocaine, an amide-type regional anesthetic, has been an important medication in the field of anesthesia since its clinical approval. Recently, lidocaine has emerged as a powerful immunomodulatory agent beyond its classical anesthetic properties. This review has summarized the recent basic and clinical studies with sufficient evidence on the multifaceted effects of lidocaine on both innate and adaptive immune cells, including macrophages, neutrophils, eosinophils, basophils, natural killer (NK) cells, mast cells, dendritic cells (DCs), monocytes, and T lymphocytes. We have also detailed how lidocaine affects critical cellular processes, such as cellular polarization, cytokine production, phagocytosis, and apoptosis, through multiple signaling pathways, including NF-κB, TLR4/p38 MAPK, voltage-sensitive sodium channels, HIF1α, TGF-β/Smad3, AMPK-SOCS3, TBK1-IRF7, and G protein-coupled receptors. These immunoregulatory effects of lidocaine are dependent on its concentration, duration of action, and the microenvironment. The immunomodulatory actions of lidocaine may contribute to its potential therapeutic value in various settings of diseases, such as cancer, sepsis, acute lung injury, asthma, organ transplantation, ischemia–reperfusion injury (IRI), and diabetes. We propose that lidocaine can be repurposed as an immunomodulator for treating immune-mediated inflammatory diseases. However, future research should define optimal dosing strategies, validate its mechanisms of action in clinical trials, and explore its novel clinical applications as a complementary immunotherapy. Full article

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance. Full article

Background and Objectives: Toll-like receptors (TLRs) are pattern recognition receptors with an essential role in regulating both the innate and adaptive immune response. Given their pleiotropic effects in mounting an immune response, previous studies have proposed targeting these TLRs might render alternative strategies for cancer therapy. Synthetic immune response modifiers, such as imidazoquinolines, stimulate the immune cells by activating Toll-like receptors, particularly TLR7/8 receptors, consequently mounting an immune response. Agonists of this class activate, via TLR-mediated signaling, dendritic and B cells, as well as myeloid cells and T cells, thus exhibiting good prospects for cancer immunotherapy. In the present study, we sought to evaluate the effect of imiquimod and gardiquimod, two TLR 7 and 7/8 agonists, respectively, on tumor growth and phenotype of NK cells associated with melanoma. Materials and Methods: We generated a syngeneic model of melanoma in C57BL/6J mice by subcutaneously injecting murine melanoma cells and monitoring tumor growth. Starting on day 8 or 14, we applied TLR agonists either intratumorally or topically and followed the tumor dynamics and NK cell-associated pattern. Results: Our results suggest that both TLR agonists displayed an antitumor effect along with a phenotypically activated profile of NK cells. Both imiquimod and gardiquimod treatment inhibited tumor growth, with gardiquimod showing an increased potency compared to imiquimod. Conclusions: This implies that TLR agonists like imiquimod and gardiquimod could serve as neoadjuvant, adjuvant, or complementary immunotherapeutic agents in melanoma therapy. Full article

MICB-targeting CAR-NK (chimeric antigen receptor-modified natural killer cells) therapy may serve as off-the-shelf immunotherapy. We designed soluble Anti-MICB-scFv blocks tumor immune evasion targeting the MICB antigen, thereby enhancing CAR-NK cytotoxicity while reactivating endogenous immune attacks against malignancies. The Anti-MICB-CAR includes two Anti-MICB-scFv connected by an F2A linker, the CD8 hinge and transmembrane domain, the 4-1BB co-stimulatory domain, the CD3ζ activation domain, and IL-15. The expression efficiency of Anti-MICB-CAR in NK cells was investigated by flow cytometry; ELISA demonstrated that Anti-MICB-CAR-NK secreted free Anti-MICB-scFv and detected IL-15 secretion. Flow cytometry and CCK8 were utilized to study Anti-MICB-CAR-NK on tumor cell viability. The PANC-1 xenograft model was established in order to elucidate the anti-tumor effects of Anti-MICB-CAR-NK in vivo. In vitro investigations have demonstrated that the treatment of tumor cells with Anti-MICB-CAR-NK supernatant + NK cells or Anti-MICB-CAR-NK cells not only significantly increased the cytotoxic activity of tumor cells, but also secreted and produced higher levels of IL-15, IFN-γ, TNF-α, perforin, and granzyme B compared with NK cells. Anti-MICB-CAR-NK cells exhibit strong cytotoxic activity against tumor cells with high MICB expression. In vivo, Anti-MICB-CAR-NK cells exhibited a substantial inhibitory effect on tumor growth. The IHC results reveal that Anti-MICB-CAR-NK cells show a more pronounced ability to infiltrate the tumor. We demonstrated the successful expression of Anti-MICB-CAR in NK cells, which enhances the anti-tumor activity of NK cells both in vitro and in vivo. This stress ligand-targeting approach provides a promising strategy for solid tumors. Full article

Chimeric antigen receptor (CAR) cell therapies have revolutionized cancer immunotherapy by enabling targeted and potent antitumor immune responses. However, clinical challenges such as limited efficacy in solid tumors, severe toxicities including cytokine release syndrome (CRS), and manufacturing complexities restrict their broader use. Recently, CAR cell-derived exosomes (CAR-Exos) have emerged as promising cell-free therapeutic alternatives that retain the key antitumor functionalities of their parent cells while potentially overcoming the limitations of live cellular therapies. These nanoscale vesicles can deliver bioactive CAR molecules, cytotoxic proteins, and immunomodulatory cargo, enabling targeted tumor cell killing with reduced systemic toxicity and offering “off-the-shelf” applicability. This review comprehensively explores the biology, engineering, and therapeutic potential of CAR-Exos derived from T cells, natural killer (NK) cells, and other immune effectors. We discuss advances in isolation, characterization, and cargo profiling techniques, as well as preclinical and early clinical data supporting their application. Further, we address translational challenges including large-scale production, biodistribution, and immune evasion in tumor microenvironments. Combining cellular and exosomal CAR platforms holds promise to enhance efficacy and safety in cancer treatment, representing a frontier in targeted immunotherapy. Full article

Major histocompatibility complex class I-like related gene A (MICA) is the most polymorphic non-classical HLA gene. MICA proteins are expressed at low levels on the surface of normal cells but are highly expressed on the surface of tumor cells. Its most important biological function is to bind to activating receptors on the surface of natural killer (NK) cells or CD8+ T cells, then activate these immune cells to exert immune killing effects. Multiple studies have shown that the amino acids at specific loci in the MICA molecule can significantly affect its binding ability to NKG2D. The binding strength of MICA-NKG2D significantly affects the anti-tumor effect of NK cells in the body and the prognosis of many tumor patients. However, the strong MICA-NKG2D interaction can trigger negative feedback against this immune response by down-regulating the expression of NKG2D or generating soluble MICA, weakening the overly intense immune response. Therefore, simply evaluating the intensity of the anti-tumor immune response from the perspective of the amino acid polymorphism of MICA affecting its binding ability to NKG2D also has limitations. We review the effects of MICA amino acid polymorphism on the affinity of the NKG2D signal pathway and analyze in detail the specific role of MICA amino acid polymorphism in tumor immunity. The study provides a reference for understanding the mechanism of anti-tumor immune response by NK cells or other immune cells, as well as a theoretical basis for considering the MICA-NKG2D signal axis for anti-tumor immune therapy in future clinical practice. Full article

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. However, the inflammatory mediators that causally drive disease progression remain incompletely defined. In this study, we used a multi-omics approach that combined single-cell RNA sequencing, spatial transcriptomics, pseudotime trajectory analysis, cell-to-cell communication analysis, and Mendelian randomization (MR) to investigate the role of tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in DKD development. Findings were further validated in zebrafish embryos depleted of pdx1, an established model of DKD. Spatial transcriptomic analysis showed that TNFRSF1A is enriched in cortical kidney regions. Pseudotime analysis revealed progressive immune reprogramming, with an early predominance of T and NK cells and gradual shift to myeloid infiltration and B-cell expansion. Cell-to-cell communication analysis highlighted IL-1β and related signaling pathways that increase NF-κB activity. Mendelian Randomization analysis, complemented by PPI network mapping, identified TNFRSF1A (OR = 1.78, 95% CI: 1.17–2.71, p = 0.007) as a gene with genetic evidence supporting a causal association. Consistent with the human data, experiments in zebrafish showed that TNFRSF1A expression increases significantly following pdx1 knockdown (p = 0.0025). Together, these findings support a role for TNFRSF1A in immune microenvironment reprogramming in DKD, while not excluding the involvement of additional regulatory pathways. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article

Female cancers, including breast and gynecological malignancies, are among the most prevalent oncological conditions worldwide. Advances in screening, diagnosis, and treatment have markedly improved survival, resulting in a growing population of female cancer survivors. Consequently, long-term health and quality of life have become essential aspects of comprehensive cancer care. Among survivorship issues, sleep disturbances—particularly insomnia—are highly prevalent and associated with adverse outcomes including mood and cognitive impairment, fatigue, immune and cardiometabolic dysregulation, and reduced adherence to therapy. Insomnia, defined as difficulty initiating or maintaining sleep or experiencing poor sleep quality with daytime impairment, affects 6–10% of the general population and is more common in women. In cancer survivors, poor sleep quality appears to be three times more frequent, reaching 62% in breast cancer survivors, although these data may be underestimated, especially for other cancer types, due to the small sample size and heterogeneity of the studies. The pathogenesis of insomnia in female cancer patients is multifactorial, involving cancer-related inflammation, hypothalamic–pituitary–adrenal axis dysregulation, neuroimmune alterations, treatment effects, psychological distress, and behavioral factors. Hormonal disruption plays a central role, as oncological treatments are often the cause of iatrogenic menopause, leading to vasomotor symptoms, mood and cognitive disturbances, sexual dysfunction, and genitourinary complaints, all contributing to sleep disruption. Importantly, estrogens and progesterone independently regulate sleep–wake pathways via central mechanisms, influencing sleep quality even in the absence of vasomotor symptoms. Management requires a multidisciplinary approach integrating oncology, gynecology, and sleep medicine. Cognitive Behavioral Therapy for Insomnia (CBT-I) is first-line, while pharmacologic options include benzodiazepines, Z-drugs, SSRIs/SNRIs, melatonin, or new medication like DORAs. Menopausal hormone therapy (MHT) should be considered for premature menopause management in selected women without contraindications, improving both vasomotor symptoms and sleep quality. Emerging neurokinin receptor (NK-R) antagonists show promise, and ongoing trials suggest significant potential even in breast cancer survivors. Full article

Chimeric antigen receptor (CAR)-T cell therapies represent a promising therapeutic approach for refractory autoimmune diseases. Although autologous CAR-T cells have achieved success thus far, they require expensive, individualised manufacturing, limiting their commercialisation potential. Allogeneic alternatives could overcome these scalability barriers, providing ‘off-the-shelf’ treatments, although they raise the issues of graft-vs-host reactions and host-mediated rejection. To mitigate such risks, gene-edited αβ T cells or non-alloreactive host cells (e.g., NK cells, γδ T cells) may be used. This review evaluates evidence of the functionality and commercial potential of various allogeneic CAR-T solutions for autoimmunity. Searches were conducted of PubMed, EMBASE and Web of Science to extract clinical and preclinical studies of allogeneic CAR-T cells, for the treatment of autoimmune diseases and B or T cell malignancies. In light of the paucity of data on autoimmune disease, the latter were included to facilitate extrapolation to the autoimmune setting. A total of 107 studies were included. The available clinical outcomes of efficacy and safety, as well as preclinical key findings, are reported. Current developments and potential future improvements for safety, effectiveness and cost-effective manufacture are then discussed. The findings of this review demonstrate the promising therapeutic potential of allogeneic CAR-T for autoimmune disease, with scope for the further optimisation of safety and scalable manufacture to facilitate commercialisation. Full article

Human leukocyte antigen (HLA)-E, a non-classical class I molecule with limited polymorphism, bridges innate and adaptive immunity. Traditionally, the role of HLA-E had been associated with regulating natural killer (NK) cell activity via CD94/NKG2 receptors, by presenting self-peptides derived from the leader sequence of HLA-I. Recent findings reveal its ability to present pathogen-derived peptides to CD8⁺ T cells, eliciting unconventional cytotoxic responses. This review examines the expanding role of HLA-E-restricted T cells in viral and bacterial infections and their capacity to recognize diverse microbial peptides and enhance immune response when classical HLA pathways are impaired. We also highlight key advances in immunotherapy and vaccine development, including CMV-vectored platforms, donor-unrestricted TCR-based strategies, and peptide prediction algorithms. The minimal polymorphism of HLA-E, its resistance to viral immune evasion, and its ability to present conserved pathogen peptides position it as a promising target for universal vaccines and next-generation immunotherapies. Understanding these unconventional roles may pave the way for broadly applicable immunotherapies and vaccines against infectious diseases. Full article