Search Results (2,606)

Background: Cytomegalovirus (CMV) reactivation is a major complication after hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells help control CMV through killer-cell immunoglobulin-like receptors (KIRs) and their HLA ligands, but donor-derived CMV-specific T-cells may confound the interpretation of NK-mediated effects. Methods: We analyzed 276 HLA-matched (10/10) adults receiving ATG-based T-cell-depleted myeloablative HSCT with a known donor and recipient CMV serostatus. The donor and recipient KIR genotypes were scored by the Cooley B-content score (0–4; ≥2 = high). Clinically significant CMV reactivation (plasma viral load > 25,000 IU/mL, the institutional threshold for pre-emptive therapy) was analyzed with Fine–Gray competing-risks regression, stratified by the donor–recipient serostatus. Results: In seronegative-donor/seropositive-recipient (D−R+) pairs (n = 68), a high donor KIR B-content score was associated with a significantly lower reactivation risk (sub-hazard ratio, 0.46; 95% CI, 0.24–0.91; p = 0.024). No effect was seen in D+R+ pairs (n = 82; SHR, 0.65; p = 0.241); D+R− (n = 28) had too few events to model. A donor Tel-AA/recipient Tel-B+ mismatch was independently associated with a higher reactivation risk (adjusted HR, 2.41; 95% CI, 1.33–4.37; p = 0.004). The overall survival was unaffected in either stratum. Conclusions: A high donor KIR B-content score protects against CMV reactivation in D−R+, but not D+R+, HSCT recipients, consistent with NK dominance when CMV-specific donor T-cells are sparse. A specific donor–recipient telomeric mismatch independently modifies the risk. Donor KIR profiling warrants prospective evaluation in donor-selection algorithms. Full article

Background: DNA Ligase 4 (LIG4) catalyzes the final ligation step during V(D)J recombination. Biallelic pathogenic variants in LIG4 cause severe combined immunodeficiency (SCID), a life-threatening immunodeficiency characterized by the lack of mature T and B cells. Case Presentation: An 18-year-old male exhibited widespread verrucous and keratotic cutaneous lesions across the face, neck, and extremities. The proband manifested early-onset short stature, chronic malnutrition, recurrent pulmonary infections with bronchiectasis, chronic diarrhea, and bilateral tenosynovitis. Immunophenotyping revealed persistent panhypogammaglobulinemia, absent B cells, reduced T and natural killer (NK) cells, and nearly undetectable naïve T cells. Both α-HPV and β-HPV were detected in the cutaneous lesions. Compound heterozygous LIG4 variants (hg19, NM206937.2, c.833G > T; p.Arg278Leu inherited from the mother; c.833G > A; p.Arg278 His inherited from the father) were identified. Conclusions: This study reports a proband with LIG4 syndrome presenting with rare phenotypes of multiple viral warts and combined lymphopenia of T, B, and NK cells. This proband harbors compound heterozygous variants at the same codon (c.833G), which not only confirm the clinical diagnosis but also enrich the known phenotypic spectrum of LIG4 syndrome. Full article

Breast cancer is the most common cancer in women, causing more than 600,000 deaths every year. The human microbiome is increasingly recognized as a key regulator of cancer initiation, progression, and therapeutic response. Postbiotics—defined as non-viable microbial cells and/or their structural components and metabolites that confer health benefits—are emerging as promising and safer alternatives to live probiotics in oncology. This review provides a comprehensive mechanistic overview of the potential role of postbiotics against cancer, with a specific focus on breast cancer. Preclinical evidence demonstrates that selected postbiotics exert dose- and time-dependent anticancer effects against multiple breast cancer subtypes by modulating key oncogenic pathways (such as PI3K/AKT and NF-κB) and inducing epigenetic regulation through histone deacetylase inhibition. Beyond direct effects on tumor cell proliferation and apoptosis, postbiotics influence the breast cancer microenvironment by reshaping cytokine networks, suppressing pro-metastatic inflammation, and enhancing antitumor immune responses through the activation of NK cells and T cells. We also provide emerging links between microbiome composition, estrobolome activity, and breast cancer subtype-specific biology. Despite these encouraging findings, the clinical translation of postbiotics in oncology remains limited. Currently, only one registered clinical trial investigates postbiotics in the oncology setting (melanoma), and no clinical trials have specifically evaluated postbiotics in breast cancer patients. This highlights a substantial translational gap between preclinical evidence and clinical application. Accordingly, well-designed, tumor-specific clinical trials are urgently needed to validate the safety, efficacy, and therapeutic potential of postbiotics as novel strategies in personalized breast cancer management. Full article

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8⁺ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8⁺ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8⁺ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8⁺ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8⁺ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8⁺ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8⁺ T cells. Conversely, activated CD8⁺ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8⁺ T cell-derived vesicles. Full article

Systemic sclerosis (SSc) is a rare, clinically heterogeneous connective tissue disease defined by the triad of autoimmunity, microvasculopathy, and fibrosis of the skin and internal organs. Among the immune effectors implicated in SSc, B cells have moved from being regarded mainly as the source of disease-defining autoantibodies to being recognized as multifunctional drivers of disease through antibody-independent mechanisms. This review summarizes current understanding of B-cell biology in SSc across three domains. First, we consider the classical role of B cells as antibody-producing cells, including the diagnostic and prognostic value of SSc-specific autoantibodies, the evidence for polyclonal B-cell activation and altered B-cell homeostasis, and the contested question of autoantibody pathogenicity. Second, we examine antibody-independent functions, focusing on cytokine production by effector and regulatory B-cell subsets, the B-cell-activating factor (BAFF) axis, antigen presentation, and T-cell co-stimulation, together with the imbalance between pro-inflammatory effector B cells and interleukin (IL)-10-producing regulatory B cells that characterizes active disease. Third, we review B cells as therapeutic targets, from the rituximab experience—including the randomized DESIRES trial and its open-label extension—through anti-BAFF strategies to the emerging use of CD19-directed chimeric antigen receptor (CAR) T-cell and CAR-natural killer (NK) cell therapies that achieve deep, durable B-cell depletion. We conclude by highlighting unresolved questions, including patient selection, the balance between depleting pathogenic and protective B-cell subsets, biomarker development, and the long-term safety of deep B-cell depletion. A B-cell-centered view of SSc pathogenesis provides a coherent framework that links autoimmunity to fibrosis and is increasingly translatable into the clinic. Full article

Hydrogel-enabled adoptive cell therapy (ACT) offers a localized and controllable strategy for improving cellular immunotherapy in solid tumors. Hydrogels can enhance cell retention and persistence, support immune cell function within the tumor microenvironment, and reduce systemic toxicity associated with broadly delivered immune stimulants. However, delivery of living immune cells imposes practical constraints on hydrogel selection, including cytocompatible encapsulation, minimal handling and injection stress, adequate transport of oxygen and soluble cues, and an appropriate balance between local retention and timely cell egress. This review summarizes natural, synthetic, and hybrid hydrogel platforms and compares physical/supramolecular assembly, covalent and enzymatic crosslinking, and photo-crosslinking. Injectable in situ-forming depots and shear-thinning/self-healing gels are highlighted for locoregional administration. Key design and reporting dimensions of hydrogels are linked to immune cell outcomes relevant to ACT. These properties include mechanics and viscoelasticity, porosity and mass transport, degradability and remodeling, bioadhesion and extracellular matrix (ECM) mimicry, and immunogenicity versus immune shielding. Finally, a cell-type-tailored framework is presented for chimeric antigen receptor T (CAR-T), T cell receptor-engineered T (TCR-T), and tumor-infiltrating lymphocyte (TIL) products, natural killer (NK) cells, and dendritic cells (DCs) or macrophage/monocyte-derived effectors. Distinct biological requirements are used to motivate corresponding material architectures and cue presentation strategies. The review also provides quantitative reporting guidance, identifies evidence gaps for γδ T cells, and discusses in vivo validation, combination ACT strategies, and translational handling constraints. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory disorder characterized by the functional engraftment of endometrial-like stroma and glands outside the uterine cavity, encompassing a heterogeneous phenotypic spectrum that ranges from deep infiltrating lesions to subtle, atypical or non-pigmented peritoneal implants. Emerging evidence suggests an association between endometriosis and cutaneous melanoma. The aim of this study was to evaluate whether women with endometriosis have an increased risk of developing melanoma and to explore potential biological mechanisms underlying this association. This review was conducted in accordance with PRISMA guidelines. A comprehensive search of PubMed/MEDLINE, Scopus, and the Cochrane Library was performed for studies published in English up to 1 February 2025. Eligible studies were restricted to cohort and casecontrol designs evaluating the association between histopathologically radiologically verified endometriosis comprising distinct phenotypes and subtle atypical lesions and histologically confirmed cutaneous melanoma. Two independent reviewers executed study selection based on these strict eligibility criteria, and due to marked clinical heterogeneity, data were synthesized qualitatively. A total of 326 records were identified, of which 17 studies met the inclusion criteria. Genetic and biomolecular evidence revealed shared susceptibility loci and common molecular pathways, including TP53, PTEN, CDKN2A, and estrogen receptor mediated signaling, suggesting a biological link between the two conditions. Epidemiological studies consistently reported a modestly increased risk of melanoma in women with endometriosis, with hazard ratios ranging from 1.50 to 1.82 (95% Confidence Interval [CI]: 1.21–2.41). This association appeared more pronounced in younger women and in those with a personal or family history of dysplastic nevi or melanoma. Limited data also suggest a reverse association, with increased occurrence of endometriosis among women with melanoma. Endometriosis and melanoma share distinct genetic architectures, characterized by shared susceptibility loci at the chromosome 9p21 region (encompassing CDKN2A/B), alongside convergent hyperestrogenemic signaling via estrogen receptor-beta (ERβ) and systemic natural killer (NK) cell immunotolerance axes. These shared molecular pathways support a biologically plausible correlation, although causal links remain unproven due to pervasive study heterogeneity and surveillance biases. Current evidence suggests a modest epidemiological link; however, heterogeneity among studies limits definitive conclusions. Full article

Refractory celiac disease (RCeD) is a rare but severe complication of celiac disease characterized by persistent or recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, after exclusion of ongoing gluten exposure, alternative enteropathies, and overt lymphoma. RCeD comprises two biologically distinct entities. RCeD-I is associated with phenotypically normal, polyclonal intraepithelial lymphocytes and generally reflects persistent gluten-independent mucosal inflammation with a relatively favorable prognosis. RCeD-II is defined by expansion of aberrant clonal intraepithelial lymphocytes lacking normal surface T-cell markers and is increasingly regarded as a low-grade intraepithelial lymphoma or in situ lymphomatous disorder, with substantial risk of progression to enteropathy-associated T-cell lymphoma (EATL). Mechanistic studies identify epithelial stress, IL-15-driven IEL survival, stromal and innate immune amplification, and cytotoxic epithelial injury as central drivers of refractory mucosal damage. In RCeD-II, aberrant IELs acquire a hybrid T/NK-like phenotype, persist through anti-apoptotic IL-15/JAK–STAT signaling, and induce enterocyte killing, while molecular alterations involving JAK1, STAT3, JAK/STAT regulators, NF-κB signaling, epigenetic regulators, and chromosomal abnormalities support stepwise lymphomagenesis. Recent single-cell multiomic studies further reveal genetically altered intestinal lymphocyte clones and intratumoral heterogeneity across the RCeD-II–EATL continuum. From a nutritional immunology perspective, RCeD illustrates a setting in which removal of the initiating dietary antigen is insufficient to restore mucosal immune homeostasis. This review summarizes the pathogenic processes that distinguish RCeD-I from RCeD-II and link failed mucosal recovery after gluten withdrawal to persistent immune-mediated epithelial injury, aberrant IEL expansion, clonal evolution, and lymphoma progression. Full article

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) involves coexisting inflammatory and hemostatic dysregulation contributing to thromboembolic and bleeding risk. Ten-eleven translocation (TET1-3) proteins regulate immune-cell phenotype, but their relationship to plasma coagulation parameters in HFrEF is poorly defined. We aimed to determine whether TET1-3 protein expression in peripheral blood leukocyte subpopulations is associated with routinely available plasma coagulation parameters in HFrEF, and whether associations differ by direct oral anticoagulant (DOAC) exposure and clinical phase. Methods: In this cross-sectional, observational, two-center study, 107 patients with HFrEF were enrolled (39 receiving a DOAC, non-randomized; 68 not receiving a DOAC, of whom seven received a vitamin K antagonist and 61 received no oral anticoagulant). TET1-3 protein expression was assessed by flow cytometry in T lymphocytes, B lymphocytes, natural killer (NK) cells, monocytes, and granulocytes, expressed as the ratio of test-to-negative-control geometric mean fluorescence intensity. Associations with activated partial thromboplastin time (aPTT) and international normalized ratio (INR) were analyzed using nonparametric tests and Spearman correlations; DOAC samples were drawn at steady-state trough. Results: DOAC-treated patients constituted a distinct clinical subgroup (older, predominantly AF/AFL) and showed longer aPTT and higher TET expression in selected immune-cell subsets; these between-group differences cannot be attributed to DOAC therapy. Patients with aPTT at or above the median showed higher TET expression in T cells, B cells, NK cells, and selected leukocyte indices, whereas INR-based stratification did not. In continuous analyses, TET indices showed multiple moderate positive Spearman correlations (R = 0.25–0.49) with both aPTT and INR—with INR showing the strongest single association—and no associations with composite inflammatory indices (NLR, SII, SIRI); all comparisons were exploratory and uncorrected for multiplicity. Associations appeared stronger in stable than in worsening HFrEF (exploratory). Conclusions: Peripheral leukocyte TET protein expression was associated with plasma coagulation parameters in HFrEF; the aPTT-specific pattern was confined to the categorical (median-split) analysis, whereas continuous analyses showed associations with both aPTT and INR. Because of the cross-sectional design, moderate sample size, and potential confounding by indication, these findings should be considered hypothesis-generating. TET-related immune-cell phenotyping may capture a non-redundant immune–coagulation signal in HFrEF and warrants prospective validation. Full article

HER-positive cancers comprise a heterogeneous group of malignancies driven by dysregulated activation of the human epidermal growth factor receptor (HER/ERBB) family. While chimeric antigen receptor (CAR) T-cell therapies targeting HER2 have demonstrated potent anti-tumor capabilities, their clinical translation remains hampered by safety hurdles and antigen escape. We developed a modular “Targeted Chimeric Artificial Reporter” (TcAR) system using the natural epidermal growth factor (EGF)-like binding domains of neuregulin-1 (NRG1) isoforms to decode complex HER dimerization profiles. Leveraging the superior targeting plasticity of the β-isoform, we engineered NRG1β-based CAR-T and CAR-natural killer (NK) cells. Our study demonstrates that NRG1β-directed therapy overcomes therapeutic antigen escape in HER2-depleted models and exerts potent anti-tumor activity within complex three-dimensional (3D) tissue microenvironments ex vivo, exhibiting a significantly safer, muted inflammatory profile compared to clinical standards. Full article

Stem cell-derived β (SC-β) cells are a promising therapy for type 1 diabetes (T1D), but their long-term efficacy is limited by immune-mediated graft rejection. Platelet-derived exosome product (PEP) has emerged as a novel immunomodulatory agent, although its effect on SC-β cell xenograft rejection remains unclear. Here, we evaluated PEP in stimulated human peripheral blood mononuclear cells (PBMCs) and in an immunocompetent mouse model of SC-β cell transplantation under the kidney capsule. Immune-related gene expression was assessed by quantitative PCR, immune cell infiltration by immunofluorescence, and graft function by circulating human insulin. In vitro, PEP reduced NK-cell-associated gene expression, including NK1.1, EOMES, and KLRK1, and increased IL-10 expression. In vivo, untreated SC-β cell xenografts showed progressive immune infiltration and loss of detectable human insulin by day 14, whereas PEP-treated grafts retained detectable insulin through day 14 across co-transplantation, pretreatment, and systemic administration strategies. PEP co-transplantation delayed, but did not prevent, xenograft rejection, with graft loss observed by day 21. This delay was associated with reduced NK1.1+ cell infiltration and lower expression of selected inflammatory and rejection-associated markers, including NK1.1, Nos2, and Nlrp3. These findings suggest that PEP modulates graft-associated immune responses and may serve as an adjunct immunomodulatory strategy for stem cell-based therapies for type 1 diabetes. Further studies are needed to evaluate sustained graft durability, safety, and translational efficacy. Full article

Background and objective: Natural killer (NK) cells are a subset of CD3⁻CD56⁺ lymphocytes that can recognize and destroy virus-infected and cancerous cells. Infection is the main factor contributing to morbidity and mortality in individuals with multiple myeloma (MM). Therefore, this study was conducted to develop a framework for assessing the association between NK cell subsets (CD56bright and CD56dim) and infections in patients with newly diagnosed multiple myeloma (NDMM). Methods: Peripheral blood samples were obtained from 47 NDMM patients, and NK cell immunophenotype analysis was performed using flow cytometry. Screening for infection was based on the pathogens and combined clinical symptoms. Results: NDMM patients exhibited a significant increase in the overall frequency of circulating NK cells (p = 0.001) when compared to healthy controls. Clinically, infectious complications were observed in 31% of the NDMM patients, with viral infections accounting for 19.1% and bacterial infections for 12.7%. Interestingly, phenotypic analysis revealed a marked shift among NK cell subsets, characterized by an expansion of the CD56bright subset (p = 0.01) and a concurrent reduction in the CD56dim subset (p = 0.01). Additionally, NDMM patients who developed infections had significantly lower NK cell percentages, whereas those without infections showed higher levels, clustering at the upper end. Conclusions: These findings suggest a skewing of the NK cell population toward the CD56bright phenotype. According to the results, NDMM patients should be closely monitored for infection. Full article

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder driven by epidermal barrier defects and dysregulated Th2 cell responses. While therapies primarily address adaptive immunity, the role of Natural Killer (NK) cells remains underappreciated. This review analyzes NK cell dysfunctions in AD pathogenesis, evaluating their contributions to compromised skin immunity, microbial dysbiosis, and secondary infections. Accumulating evidence reveals a systemic deficiency of mature, cytotoxic CD56^dim and NKp80+ NK cell subsets in peripheral blood, correlating with disease severity. Within the cutaneous microenvironment, Staphylococcus aureus subverts defenses by utilizing leukocidins to lyse mature NK cells, while superantigens drive an aberrant, pro-inflammatory CD57⁻NKG2+ phenotype, exacerbating inflammation. Furthermore, localized exhaustion of functional NK cells and failure to produce interferon-gamma directly explains AD patients’ unique susceptibility to severe viral complications like eczema herpeticum. Importantly, treatments such as dupilumab and gut microbiota transplantations demonstrate that these NK cell aberrations are reversible, shifting immunity toward a normalized regulatory state. In conclusion, the NK cell compartment represents a vital regulatory axis bridging innate and adaptive immunity. Targeting this axis, particularly through IL-15 superagonists, offers a promising therapeutic frontier to suppress type 2 inflammation and restore antimicrobial defenses. Full article

Introduction: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT), is a rare and aggressive lymphoma for which real-world data from resource-limited settings remain scarce. This study evaluated the efficacy and safety of frontline multimodal treatment strategies for localized ENKTL-NT. Methods: We retrospectively analyzed 62 patients with localized ENKTL-NT treated at the Vietnam National Cancer Hospital between May 2019 and June 2025. Patients received concurrent chemoradiotherapy followed by VIPD or VIDL, or sequential chemoradiotherapy with GELOX/PGEMOX. Treatment responses, survival outcomes, and toxicities were assessed. Results: The median age was 44 years, and 67.7% of patients had stage I disease. Baseline EBV-DNA positivity was detected in 46.8%, while 54.8% had PINKE scores of 1–2. The overall response rate was 93.5%, including an 85.5% complete response rate. Grade 3–4 neutropenia was the most common adverse event (18.7%). The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 76.3% and 79.5%, respectively. Multivariable Cox analysis identified PINKE risk stratification as an independent predictor of both PFS and OS. Conclusions: Frontline multimodal treatment strategies achieved high response rates, favorable survival outcomes, and manageable toxicities in localized ENKTL-NT. The PINKE score remained an important prognostic factor, supporting risk-adapted treatment selection in routine clinical practice. Full article

Male hypogonadism is associated with metabolic and cardiovascular comorbidities, and emerging evidence implicates testosterone deficiency in immune dysregulation that may elevate cancer risk. To review current evidence on the relationship between male hypogonadism, immune function, and cancer risk, focusing on mechanisms linking testosterone deficiency to immune suppression and oncologic outcomes. PubMed/MEDLINE, Google Scholar, and SciSpace were systematically searched (through April 2026) using predefined search strings. After removal of duplicates (n = 1535 records screened), 156 full-text articles were assessed for eligibility; 20 studies met predefined inclusion criteria (comprising 4 experimental studies, 4 prospective/RCT studies, 7 observational studies, and 5 reviews used as secondary literature) and were included in a narrative synthesis. Testosterone deficiency was consistently associated with elevated IL-6, TNF-α, IL-1β, and CRP, impaired neutrophil maturation, and reduced NK-cell cytotoxicity. Androgen deprivation augmented thymic output and anti-tumor T cell responses in prostate cancer models, yet promoted chronic inflammation in other contexts. Epidemiologically, low testosterone correlated with increased colorectal cancer risk and poorer survival in advanced malignancies; the prostate cancer relationship followed a paradoxical saturation model. The immunological consequences of hypogonadism are context-dependent. Testosterone deficiency drives pro-inflammatory signaling that may promote carcinogenesis, while androgen-mediated immunosuppression can paradoxically impair anti-tumor surveillance. No simple linear relationship exists between hypogonadism and cancer risk via immune suppression. Prospective studies are needed to guide clinical decisions on testosterone replacement therapy in hypogonadal men. Full article