Search Results (2,182)

Background: Soft tissue sarcomas (STSs) are a rare and heterogeneous group of mesenchymal tumors with limited response to current therapies, particularly in advanced stages. STS tumors were traditionally considered “cold” tumors, characterized by limited immune infiltration and low immunogenicity. However, emerging evidence is challenging this perception, highlighting a potentially critical role for the immune system in STS biology. Objective: Building on our previous findings suggesting impaired natural killer (NK) cell activity in STS patients, we aimed to perform an in-depth characterization of peripheral NK cells in STS. Methods: Peripheral blood samples from STS patients and sex- and age-matched healthy donors were analyzed to assess NK cell degranulation, IFNγ production, and receptor repertoire. Results: Functional assays revealed a notable reduction in both degranulation and IFNγ production in NK cells from STS patients. STS patients also exhibited dysregulated expression of activating and inhibitory NK cell receptors. Principal component analysis (PCA) identified CD27 and NKp44 as critical markers for distinguishing STS patients from healthy donors. Increased CD27 expression represents a shift towards a more regulatory NK cell phenotype, and we found that CD27 expression was negatively correlated with NK cell degranulation and IFNγ production. ROC curve analysis demonstrated strong potential to distinguish between the groups for both CD27 (AUC = 0.85) and NKp44 (AUC = 0.94). Conclusion: In conclusion, STS patients exhibited impaired NK cell function, altered receptor repertoire, and a shift towards a less cytotoxic and more regulatory phenotype. Full article

In this review, we explore the complexities of objectively assessing the response to immunotherapy in mycosis fungoides (MF), a prevalent form of cutaneous T-cell lymphoma. The core challenge lies in distinguishing between reactive and malignant lymphocytes amidst treatment, particularly given the absence of uniform pathological biomarkers for MF. We highlight the vital role of emerging histological technologies, such as multispectral imaging and spatial transcriptomics, in offering a more profound insight into the tumor microenvironment (TME) and its dynamic response to immunomodulatory therapies. Drawing on parallels with melanoma—another immunogenic skin cancer—our review suggests that methodologies and insights from melanoma could be instrumental in refining the approach to MF. We specifically focus on the prognostic implications of various TME cell types, including CD8+ tumor-infiltrating lymphocytes, natural killer (NK) cells, and histiocytes, in predicting therapy responses. The review culminates in a discussion about adapting and evolving treatment response quantification strategies from melanoma research to the distinct context of MF, advocating for the implementation of novel techniques like high-throughput T-cell receptor gene rearrangement analysis. This exploration underscores the urgent need for continued innovation and standardization in evaluating responses to immunotherapies in MF, a field rapidly evolving with new therapeutic strategies. Full article

The fungal component of microbiota, known as the mycobiome, inhabits different body niches such as the skin and the gastrointestinal, respiratory, and genitourinary tracts. Much information has been gained on the bacterial component of the human microbiota, but the mycobiome has remained somewhat elusive due to its sparsity, variability, susceptibility to environmental factors (e.g., early life colonization, diet, or pharmacological treatments), and the specific in vitro culture challenges. Functionally, the mycobiome is known to play a role in modulating innate and adaptive immune responses by interacting with microorganisms and immune cells. The latter elicits anti-fungal responses via the recognition of specific fungal cell-wall components (e.g., β-1,3-glucan, mannan, and chitin) by immune system receptors. These receptors then regulate the activation and differentiation of many innate and adaptive immune cells including mucocutaneous cell barriers, macrophages, neutrophils, dendritic cells, natural killer cells, innate-like lymphoid cells, and T and B lymphocytes. Mycobiome disruptions have been correlated with various diseases affecting mostly the brain, lungs, liver and pancreas. This work reviews our current knowledge on the mycobiome, focusing on its composition, research challenges, conditioning factors, interactions with the bacteriome and the immune system, and the known mycobiome alterations associated with disease. Full article

The B-cell lymphoma 2 (Bcl-2)-related ovarian killer (BOK), a member of the Bcl-2 protein family, shares a similar domain structure and amino acid sequence homology with the pro-apoptotic family members BAX and BAK. Although BOK is involved in the development of various types of cancer, its mechanism of action in breast cancer remains unclear. This study found that BOK was involved in the process of MG132, inhibiting the migration and epithelial–mesenchymal transition (EMT) of breast cancer cells induced by transforming growth factor-β. Furthermore, interfering BOK reversed the inhibition of breast cancer cell migration and the EMT process by MG132. Additional studies revealed that BOK silencing promoted the expression of EMT-related markers in breast cancer cells, while BOK overexpression inhibited EMT and migration. Using RNA-seq sequencing and Western blotting, we confirmed that the Wnt signaling pathway is involved in BOK regulating the EMT process in breast cancer cells. Therefore, we conclude that low BOK expression promotes breast cancer EMT and migration by activating the Wnt signaling pathway. This study enhances our understanding of breast cancer pathogenesis and suggests that BOK may serve as a potential prognostic marker and therapeutic target for breast cancer. Full article

Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We conducted a comprehensive literature analysis examining natural products tested in cancer organoids, immunomodulatory mechanisms from traditional models, technical advances in organoid-immune co-cultures, and standardization requirements for clinical translation. Our analysis reveals a critical research gap: no published studies have investigated natural product-mediated immunomodulation using organoid-immune co-culture systems. Even though compounds like curcumin, resveratrol, and medicinal mushroom polysaccharides show extensive immunomodulatory effects in two-dimensional (2D) cultures, and organoid technology achieves high clinical correlation for drug response prediction, all existing organoid studies focus exclusively on direct cytotoxicity. Technical challenges include compound stability, limited matrix penetration requiring substantially higher concentrations than 2D cultures, and maintaining functional immune populations in three-dimensional (3D) systems. The convergence of validated organoid-immune co-culture platforms, Food and Drug Administration (FDA) regulatory support through the Modernization Act 2.0, and extensive natural product knowledge creates unprecedented opportunities. Priority research directions include systematic screening of immunomodulatory natural products in organoid-immune co-cultures, development of 3D-optimized delivery systems, and clinical validation trials. Success requires moving beyond cytotoxicity-focused studies to investigate immunomodulatory mechanisms in physiologically relevant 3D systems, potentially unlocking new precision cancer immunotherapy approaches. Full article

Soil-transmitted helminths (STHs) and Herpes Simplex Virus type 2 (HSV-2) are highly prevalent infections with overlapping distribution, particularly in resource-poor regions. STH/HSV-2 co-infections may impact female reproductive health. However, many aspects of STH/HSV-2 co-infections, including the role of microRNAs (miRNAs) in regulating female genital tract (FGT) immunity and their potential contribution to pathologies such as chronic inflammation, impaired mucosal defense, and reproductive tract cancers remain unclear. In this study we investigated the miRNA expression profiles in murine FGT tissues following single or co-infection with Nippostrongylus brasiliensis (Nb) and HSV-2 and explored predicted miRNA-mRNA targets and pathways. An analysis of miRNA sequencing data was conducted to determine differentially expressed (DE) miRNAs between infected FGT tissues and uninfected controls. Ingenuity Pathway Analysis was conducted to predict the immune-related target genes of the DE miRNAs and reveal enriched canonical pathways, top diseases, and biological functions. Selected representative DE miRNAs were validated using RT-qPCR. Our results showed a total of eight DE miRNAs (mmu-miR-218-5p, mmu-miR-449a-5p, mmu-miR-497a-3p, mmu-miR-144-3p, mmu-miR-33-5p, mmu-miR-451a, mmu-miR-194-5p, and mmu-miR-192-5p) in the comparison of Nb-infected versus uninfected controls; nine DE miRNAs (mmu-miR-451a, mmu-miR-449a-5p, mmu-miR-144-3p, mmu-miR-376a-3p, mmu-miR-192-5p, mmu-miR-218-5p, mmu-miR-205-3p, mmu-miR-103-3p, and mmu-miR-200b-3p) in the comparison of HSV-2-infected versus uninfected controls; and one DE miRNA (mmu-miR-199a-5p) in the comparison of Nb/HSV-2 co-infected versus uninfected controls (p-value < 0.05, |logFC| ≥ 1). Core expression analysis showed that, among other canonical pathways, the DE miRNAs and their predicted mRNA targets were involved in neutrophil degranulation, interleukin-4 and interleukin-13 signaling, natural killer cell signaling, interferon alpha/beta signaling, and ISGylation. Additionally, cancer was predicted as one of the significantly enriched diseases, particularly in the co-infected group. This is the first study to provide insights into the FGT miRNA profiles following Nb and HSV-2 single and co-infection, as well as the predicted genes and pathways they regulate, which may influence host immunity and pathology. This study highlights the role of miRNAs in regulating FGT immunity and pathology in the context of STH/HSV-2 co-infection. Full article

Metastatic breast cancer (BC) spread underscores the need for novel prognostic biomarkers. This study investigated CCR4-NOT Transcription Complex Subunit 7 (CNOT7) and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in BC progression and natural killer (NK) cell resistance. In the current study, 90 female BC patients (46 non-metastatic, 44 metastatic) were analyzed. CNOT7 and LAIR-1 protein levels were measured in serum via ELISA and CNOT7 expression in tissue by immunohistochemistry (IHC). In silico tools explored related pathways. Computational analyses, including in silico bioinformatics and molecular docking, explored gene functions, interactions, and ligand binding to CNOT7 and LAIR-1. CNOT7 serum levels were significantly elevated in metastatic patients (mean 4.710) versus non-metastatic patients (mean 3.229, p < 0.0001). Conversely, LAIR-1 serum levels were significantly lower in metastatic (mean 56.779) versus non-metastatic patients (mean 67.544, p < 0.0001). High CNOT7 was found in 50% (45/90) of cases, correlating with higher tumor grade, hormone receptor negativity, and increased lymph node involvement. Elevated CNOT7 and lower LAIR-1 levels were associated with worse overall survival. Pathway analysis linked CNOT7 to the PI3K/AKT/mTOR pathway. Computational findings elucidated CNOT7′s cellular roles, gene/protein interaction networks for LAIR-1/CNOT7, and distinct ligand binding profiles. High CNOT7 levels are associated with advanced BC stages and poor clinical outcomes, which suggests its utility as a prognostic biomarker. The inverse relationship between CNOT7 and LAIR-1 provides mechanistic insights into BC progression and immune evasion, further supported by in silico investigations. Full article

Background: We have previously shown the remarkable impact of a single infusion of supercharged NK cells (sNK) in preventing and eliminating oral, pancreatic, and uterine cancers implanted in humanized BLT (hu-BLT) mice. Objective: In this report, we extended the studies to melanoma tumors to observe whether there were differences in response to sNK cells. Methods: We investigated the safety and tissue biodistribution profile of sNK cells in hu-BLT mice. This included the effect of sNK cell therapy on the peripheral blood-derived PBMCs, bone marrow, and spleen of hu-BLT mice. Results: Our investigation showed promising outcomes, as sNK cell infusions effectively inhibited melanoma tumor growth in hu-BLT mice. These potent cells not only traversed through the peripheral blood, spleen, and bone marrow but also infiltrated the tumor site, triggering in vivo differentiation of melanoma tumors. Moreover, the infusion of sNK cells increased the percentages of NK cells in the peripheral blood of hu-BLT mice, restoring cytotoxicity and IFN-γ secretion within the peripheral blood, spleen, and bone marrow of melanoma-bearing mice. Conclusions: This therapeutic approach not only reversed tumor progression but also revitalized the functionality of endogenous NK cells, potentially reversing the immunosuppressive effects induced by tumor cells in cancer patients. Full article

CD8+ T lymphocytes (CTLs) act as serial killers of infected or malignant cells by releasing large amounts of interferon-gamma (IFNγ) and granzymes. Although IFNγ is a pleiotropic cytokine with diverse immunomodulatory functions, its precise spatiotemporal regulation and role in CTL-mediated cytotoxicity remain incompletely understood. Using wild-type and granzyme B-mTFP knock-in mice, we employed a combination of in vitro approaches, including T cell isolation and culture, plate-bound anti-CD3e stimulation, degranulation assays, flow cytometry, immunofluorescence, and structured illumination microscopy, to investigate IFNγ dynamics in CTLs. IFNγ expression in CTLs was rapid, transient, and strictly dependent on T cell receptor (TCR) activation. We identified two functionally distinct IFNγ-producing subsets: IFNγ^high (IFNγ^hi) and IFNγ^low (IFNγ^lo) CTLs. IFNγ^hi CTLs exhibited an effector/effector memory phenotype, significantly elevated CD107a surface expression (a marker of lytic granule exocytosis), and higher colocalization with cis-Golgi and granzyme B compared to IFNγ^lo CTLs. Furthermore, CRTAM, an early activation marker, correlated with IFNγ expression in naive CTLs. Our findings establish a link between elevated IFNγ production and enhanced CTL cytotoxicity, implicating CRTAM as a potential regulator of early CTL activation and IFNγ induction. These insights provide a foundation for optimizing T cell-based immunotherapies against infections and cancers. Full article

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article

Immunological factors have gained growing recognition as key contributors to recurrent pregnancy loss (RPL) after in vitro fertilization (IVF), representing a major challenge in reproductive medicine. RPL affects approximately 1–2% of women trying to conceive naturally and up to 10–15% of those undergoing IVF, where overall success rates remain around 30–40% per cycle. An imbalance in maternal immunological tolerance toward the semi-allogeneic fetus during pregnancy may lead to miscarriage and implantation failure. IVF-related ovarian stimulation and embryo modification offer additional immunological complications that can exacerbate existing immune dysregulation. Recent advances in reproductive immunology have significantly deepened our understanding of the immune mechanisms underlying RPL following IVF, particularly highlighting the roles of regulatory T cells (T regs), natural killer cells, cytokine dysregulation, and disruptions in maternal–fetal immune tolerance. In order to better customize therapies, this evaluation incorporates recently discovered immunological biomarkers and groups patients according to unique immune profiles. Beyond conventional treatments like intralipid therapy and intravenous immunoglobulin, it also examines new immunomodulatory medications that target certain immune pathways, such as precision immunotherapies and novel cytokine modulators. We also discuss the debates over immunological diagnostics and therapies, such as intralipid therapy, intravenous immunoglobulin, corticosteroids, and anticoagulants. The heterogeneity of patient immune profiles combined with a lack of strong evidence highlights the imperative for precision medicine to improve therapeutic consistency. Novel indicators for tailored immunotherapy and emerging treatments that target particular immune pathways have encouraging opportunities to increase pregnancy success rates. Improving management approaches requires that future research prioritize large-scale clinical trials and the development of standardized immunological assessments. This review addresses the immunological factors in RPL during IVF, emphasizing underlying mechanisms, ongoing controversies, and novel therapeutic approaches to inform researchers and clinicians. Full article

This paper conducts a literature review on the role of natural killer cells in haploidentical hematopoietic stem cell transplantation. Theoretical concepts related to KIR genes are introduced regarding their structure, nomenclature, genetic organization, polymorphism, and inheritance pattern, types of KIR proteins and receptors, HLA ligands for KIR receptors, and the definition of different NK alloreactivity prediction models for the donor of haploidentical hematopoietic stem cell transplantation and the recipient. These models include the following and consider incompatibility: ligand–ligand, receptor–ligand, gene–gene, and KIR haplotype models or the KIR-B donor group. These models consider the presence or absence of specific ligands or receptors and/or KIR genes in the donor and recipient to predict alloreactivity. Determining the best model for predicting KIR alloreactivity and its significance in donor selection algorithms for haploidentical transplantation is still under investigation. Full article

Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer. Full article

Sleep deprivation impairs immune function, and melatonin has emerged as a key mediator in this process. This narrative review analyzes 50 studies published between 2000 and 2025 to determine the extent to which reduced melatonin synthesis contributes to immune dysregulation. Consistent sleep loss lowers melatonin levels, which correlates with elevated proinflammatory cytokines (e.g., IL-6 and TNF-α), increased oxidative stress, and reduced immune cell activity, including that of natural killer (NK) cells and CD4+ lymphocytes. Melatonin regulates immune pathways, including NF-κB signaling. It also supports mitochondrial health and helps maintain gut barrier integrity. These effects are particularly relevant in vulnerable populations, including older adults and shift workers. Experimental findings also highlight melatonin’s therapeutic potential in infections like SARS-CoV-2, where it modulates inflammatory responses and viral entry mechanisms. Despite the heterogeneity of study methodologies, a consistent correlation emerges between circadian disruption, melatonin suppression, and immune imbalance. These findings underscore melatonin’s dual role as a chronobiotic and immunomodulator. Addressing sleep loss and considering melatonin-based interventions may help restore immune homeostasis. More clinical trials are needed to determine the best dosing, long-term efficacy, and population-specific strategies for supplementation. Promoting healthy sleep is crucial for preventing chronic inflammation and diseases associated with immune dysfunction. Full article

CD226, a member of the immunoglobulin superfamily, serves as a critical regulator in various immunological processes. CD226 is expressed across immune and non-immune cells, with predominant expression being observed in natural killer (NK) cells and T cells. By engaging ligands CD155 and CD112, it orchestrates diverse signaling pathways that modulate T cell differentiation and effector functions while enhancing NK cell activation and cytotoxicity. Genetic polymorphisms and the dysregulated expression of CD226 are closely associated with susceptibility to autoimmune diseases, infectious diseases, allergic diseases, and cancer progression. Growing evidence highlight CD226’s emerging promise as a therapeutic target for immune-mediated diseases. The present work aims to review the current understanding of CD226’s role in immune responses and to comprehensively outline its multifaceted involvement in different immunological diseases, providing insights for future research to advance our mechanistic understanding of its roles in disease pathogenesis. Full article