Sepsis is a life-threatening organ dysfunction caused by dysregulated host responses to infection. As an important immune organ, the liver plays a vital role in the pathophysiological process of sepsis. When sepsis occurs, the liver exhibits unique immunological characteristics, including abnormal activation of pattern recognition receptors, loss of control of the complement system, adaptive immune regulation, and hepatic Kupffer cell polarization, which together determine the outcome of septic liver. Natural killer (NK) cells are innate immune cells with different biological characteristics in the liver than circulating NK cells. Natural killer (NK) cells assume a dual role in hepatic pathophysiology, functioning as both protectors and effectors of injury. On the protective front, these cells mediate antimicrobial defense and immunomodulation through interferon-gamma (IFN-γ) secretion, maintain vascular endothelial barrier integrity via vascular endothelial growth factor (VEGF) downregulation, and regulate hepatic inflammation through the production of anti-inflammatory cytokines such as interleukin-10 (IL-10). Additionally, their cytotoxic activity effectively suppresses viral replication within the hepatic microenvironment. Conversely, NK cells contribute to hepatocellular damage through distinct deleterious mechanisms. They elaborate tumor necrosis factor-alpha (TNF-α) and IFN-γ, thereby precipitating cytokine storm formation. Through the exogenous pathway (Fas ligand/TNF-related apoptosis-inducing ligand [FasL/TRAIL]) and the endogenous pathway (perforin/granzyme), they directly induce hepatocyte apoptosis. Furthermore, NK cells regulate ferroptosis-related gene expression-including heme oxygenase-1 (Hmox1) and solute carrier family 3 member 2 (Slc3a2)-thus driving the progression of sepsis-associated liver failure. This review describes the immunological characteristics of the liver in sepsis and the mechanisms of NK protection and damage to the liver. This study provides a new perspective for exploring immunotherapy of septic liver injury in the future.
Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (EVs), which transfer molecular signals between cells and influence immune function. Although NK cell-derived EVs (NK92-EVs) have shown the ability to directly kill cancer cells, how they shape the broader human immune response has remained unclear. Here, NK92-EVs were shown to reprogram cellular human immunity to enhance tumor cytotoxicity using single-cell transcriptomics and functional cytotoxicity assays. When human peripheral blood mononuclear cells (PBMCs) from healthy and cancer patients (who exhibit systemic dysregulation) were exposed to NK92-EVs, widespread shifts in gene activity occurred across key immune populations, notably CD8+ T cells and NK cells. These changes enhanced the cells' ability to recognize and eliminate tumor targets and were consistent across all donors. Functional depletion and enrichment experiments, together with transcriptomic profiling, provide direct evidence that NK92-EV-mediated immune reprogramming enhances NK cell-driven, MHC-I-independent tumor cytotoxicity, but not for CD4+ and CD8+ T cells. This work advances understanding of immune communication and highlights NK92-EVs as promising, cell-free candidates for the next generation of cancer immunotherapies that unite potency with clinical scalability.
Both adaptive immune cells, particularly T cells, and innate lymphoid cells, such as Natural Killer (NK) cells, play critical yet complementary roles in tumor immunity. While T cells mediate antigen-specific cytotoxic responses, NK cells provide rapid, innate recognition and elimination of transformed cells, and their interplay can significantly enhance antitumor immunity, offering potential improvements in immunotherapeutic efficacy. Recent studies indicate that NK cells are essential for recruiting type 1 conventional dendritic cells (cDC1) into the tumor microenvironment, which in turn promotes the activation and expansion of tumor-specific CD8+ T cells. Conversely, activated T cells secrete interleukin-2 (IL-2), a cytokine crucial for NK cell proliferation, survival, and cytotoxic function, establishing a positive feedback loop that amplifies immune responses against malignancies. Tumors, however, exploit immune evasion mechanisms, including modulation of the activating receptor NKG2D and its ligands MICA and MICB, to escape detection by both NK and T cells. Furthermore, these lymphocytes share important inhibitory and activating receptor pairs, such as CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E, which regulate cytotoxic potential and maintain immune homeostasis. Targeting these shared checkpoints or modulating receptor-ligand interactions represents a promising strategy to overcome tumor immune evasion. By elucidating the coordinated actions of NK and T cells and their shared regulatory pathways, novel immunotherapeutic approaches can be developed to enhance antitumor responses, improve treatment efficacy, and ultimately improve clinical outcomes for cancer patients.
Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is one of the most aggressive non-Hodgkin lymphomas characterized by NK-cell or T-cell origins, a geographic prevalence in Asian and South American populations, and Epstein-Barr virus (EBV) infection. ENKTCL used to be a fatal disease upon treatment with anthracycline-containing chemotherapies. However, the treatment paradigms for ENKTCL have evolved; consequently, patients have achieved significantly improved clinical outcomes. Today, combined-modality therapies co-targeting genomic instability and metabolic vulnerability comprise the standard of care for early stage ENKTCL, whereas therapies that include targeting of immune and metabolic dysregulation are the backbone of treatment for advanced-stage ENKTCL. New agents targeting surface antigens, oncogenic signaling pathways, and EBV are under investigation and have demonstrated promising responses. Hematopoietic stem cell transplantation is beneficial when used in therapy-responsive, high-risk patients and ENKTCL-associated hemophagocytic lymphohistiocytosis, but it is not recommended for early stage ENKTCL. Although nearly 80% of patients with newly diagnosed ENKTCL achieve long-term survival, treatment of relapsed/refractory ENKTCL is critical. Because it is now understood that EBV infection has a major role in disease progression, a deeper understanding of EBV-associated oncogenesis and alterations in the tumor microenvironment foster the development of novel therapeutic strategies, such as cellular therapies and vaccines targeting EBV. Future multicenter collaborations worldwide will be needed to further optimize mechanism-based treatment in the era of precision medicine, paving a curative pathway for this once fatal disease.
This study maps the global clinical trial landscape of cytokine-induced killer (CIK) cell therapy across malignancies and selected immune-related disorders, based on 199 interventional trials retrieved from the Informa database up to February 2026. Analysis reveals a rapidly expanding field dominated by early-phase studies, with China leading clinical translation and academic institutions as primary sponsors. Oncology trials are most frequent, particularly in lung cancer, leukemia, and hepatocellular carcinoma, while combinatorial strategies such as dendritic cell-CIK therapy or checkpoint inhibitor combinations are increasingly explored. Adjuvant and maintenance settings predominate over neoadjuvant applications, and emerging studies indicate potential extension into autoimmune and inflammatory diseases. These findings underscore the translational potential of CIK therapy, highlight evolving combination strategies, and reveal opportunities to optimize patient stratification, standardize cell preparation, and incorporate biomarker-guided approaches. Collectively, this landscape analysis highlights key trends shaping the future clinical development of CIK-based immunotherapy and informs strategic design considerations for advancing its integration into modern oncology and immunomodulatory treatments.
The prognosis of patients with metastatic/relapsed/refractory Ewing sarcoma (ES) is dismal. Natural killer (NK) cells are highly cytotoxic to ES but limited by resistance within the ES tumor microenvironment (TME). Here we sought to overcome ES resistance to NK cells by a combinatorial immunotherapy approach simultaneously enabling NK tumor-specific-targeting via chimeric antigen receptor (CAR) against a novel ES target interleukin-1 receptor accessory protein (IL1RAP), circumventing transforming growth factor beta (TGFβ)-mediated NK immunosuppression by TGFβ1-imprinting, increasing NK cell antibody-dependent cellular cytotoxicity (ADCC) via an anti-GD2 antibody dinutuximab, and improving NK cell persistence and ADCC by an IL-15 agonist, NKTR-255. Peripheral blood mononuclear cells were expanded into NK and TGFβ1-imprinted-NK (imNK) cells using antigen-presenting feeder cells co-expressing IL-21 and 4-1 BBL. Anti-IL1RAP-CAR messenger RNA was electroporated into NK or imNK cells. In vitro cytotoxicity assays were performed to investigate the efficacy of anti-IL1RAP-CAR-NK/imNK cell alone or combined with NKTR-255 and/or dinutuximab against ES cells. Xenograft mouse models of ES were used to investigate the antitumor efficacy of the combinatorial CAR-NK/imNK cell therapy against ES in vivo. Single-cell RNA sequencing and mass cytometry analyses of cells from xenograft tumors were performed to identify mechanisms of response/resistance to this combinatorial immunotherapy. We found that anti-IL1RAP-CAR-NK cells significantly and specifically enhanced NK cytotoxicity in vitro and decreased tumor growth and lung metastasis in vivo against IL1RAP+ES. TGFβ1-imprinting significantly enhanced in vitro cytotoxicity and tumor infiltration of CAR-NK cells, leading to significantly reduced tumor growth and improved animal survival in the ES orthotopic mouse model. Compared with single agent or double combinations, the triple combination of imprinted-CAR-NK (CAR-imNK) cells and NKTR-255 with dinutuximab had superior antitumor efficacy against IL1RAP+GD2+ ES. Mechanistic studies on single cells from the xenograft tumors revealed increased apoptosis of ES cells, upregulated expression of ligands to NK inhibitory receptors on ES cells, and enhanced mouse macrophage migration in the ES TME in response to the CAR-imNK+NKTR-255+dinutuximab therapy. Our preclinical data demonstrate that combinatorial innate immunotherapy leveraging tumor-targeting TGFβ1-imprinted IL1RAP-CAR-NK cells combined with an IL-15 agonist and an anti-GD2 antibody is a promising novel therapeutic strategy for targeting metastatic/relapsed/refractory ES.
SUMMARYMendel's Law of Segregation posits an equal probability for each allele to be inherited during sexual reproduction. This process, however, is subverted by killer meiotic drivers (KMDs)-selfish genetic elements that enhance their own transmission in driver+/driver- heterozygotes by selectively eliminating meiotic products lacking the driver allele. Such elements arise recurrently during evolution, and the genomic conflicts they generate are considered potent evolutionary forces shaping genome architecture and sexual reproductive systems. While documented across diverse eukaryotes-including plants, fungi, and animals-most KMDs remain molecularly uncharacterized, and their actual prevalence in nature remains elusive. In fungi, KMDs can act at two distinct life-cycle stages: by directly killing sexual spores (fungal gametes)-hence termed "spore killers"-or by targeting haploid progeny after spore germination. Fungal models have profoundly advanced our understanding of these elements. This review synthesizes current knowledge on characterized fungal KMDs (from Neurospora, Podospora, Fusarium, and Schizosaccharomyces), emphasizing their molecular basis and interplay with the host. Approaches for KMD discovery are also discussed. Growing evidence from fungi suggests that these selfish elements are likely far more prevalent than previously appreciated.
Despite promising development as emerging "off-the-shelf" therapeutics against cancer, natural killer (NK) cells still faced considerable challenges in the solid tumor microenvironment (TME), including poor penetrance and immuno-suppression. Here, we employ spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). Orthogonal analysis of human and mouse HCC tumors indicate that the expression of NR4A1, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons, and better disease-free survival in HCC. Conditional ablation of Nr4a1 in NK cells perturbs their homeostasis and accelerates tumor progression in multiple tumor models. Conversely, the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhances their anti-tumor functions. Mechanistically, downstream functional assays confirm that Nur77 activation attenuates CD36 expression in NK cells and confers resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlight the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against HCC.
Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare and aggressive malignancy, with ocular and orbital involvement representing an uncommon but clinically important presentation. Many cases are frequently misdiagnosed due to their ability to mimic common inflammatory and infectious eye conditions, resulting in delayed diagnosis and poorer clinical outcomes. This systematic review aimed to evaluate clinical outcomes and prognostic factors in ocular and orbital ENKTL. A PRISMA-compliant systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261348194) and conducted using PubMed, MEDLINE, Embase, and Cochrane Library from database inception to 19 March 2026. Twenty-eight studies comprising approximately 429 patients were included. Data were extracted on patient demographics, treatment, survival, and prognostic factors, and analysed using a narrative synthesis. Median survival ranged from six to 17 months, with high mortality and frequent reports of rapid clinical deterioration. Delayed diagnosis, advanced disease, central nervous system involvement, and relapse were associated with poorer outcomes. Non-anthracycline, asparaginase-based regimens were associated with improved disease control compared with conventional therapies, although outcomes remained poor overall. Visual outcomes were similarly unfavourable. Improved survival was associated with early recognition, prompt biopsy, and timely initiation of appropriate treatment.
In this report we highlight the emerging role of pediatric cardiac point-of-care ultrasound (POCUS) in rapidly diagnosing infective endocarditis, using a clinical case as illustration. A six-year-old girl with a known ventricular septal defect presented with worsening respiratory symptoms, fevers, abdominal pain, and decreased oral intake. Initial POCUS, performed by an emergency physician, indicated a suspicious echogenic mass in the right atrium, prompting formal echocardiography. Further imaging and cultures confirmed infective endocarditis due to methicillin-sensitive Staphylococcus aureus. This case underscores the utility of pediatric cardiac POCUS as a rapid bedside diagnostic tool for infective endocarditis in emergency settings, leading to early diagnosis and management. Although POCUS cannot replace comprehensive echocardiography, its immediate availability significantly accelerates diagnosis and management initiation, particularly in pediatric patients with congenital heart conditions who are at increased risk for the condition. Ongoing training and standardized protocols will enhance its efficacy. Clinicians should recognize the strengths and limitations of POCUS, integrating it into broader diagnostic workflows for pediatric infective endocarditis.
Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism, typically associated with identifiable risk factors such as immobilization, surgery, malignancy, or trauma. However, in young individuals without apparent triggers, underlying thrombophilic states must be investigated. Hyperhomocysteinemia is an often overlooked yet reversible metabolic risk factor contributing to thrombogenesis. We report a 31-year-old male electrician presenting with acute-onset breathlessness, pleuritic chest pain, and cough. Clinical evaluation revealed tachypnea, tachycardia, and hypoxemia. Electrocardiography demonstrated sinus tachycardia with an S1Q3T3 pattern. Arterial blood gas analysis showed hypoxemia with respiratory alkalosis. Computed tomography pulmonary angiography confirmed a significant thrombus in the right main pulmonary artery causing >50% luminal obstruction. Echocardiography revealed right heart strain. Routine thrombophilia workup was negative; however, markedly elevated serum homocysteine (>65 μmol/L) with low folate and borderline Vitamin B12 levels was noted. The patient was treated with anticoagulation and vitamin supplementation with clinical improvement. This case highlights hyperhomocysteinemia as a reversible yet under-recognized cause of unprovoked PE. Early detection and correction can significantly reduce recurrence risk and improve outcomes. RésuméL’embolie pulmonaire (EP) est une manifestation potentiellement mortelle de la thromboembolie veineuse, généralement associée à des facteurs de risque identifiables tels que l’immobilisation, la chirurgie, les cancers ou les traumatismes. Cependant, chez les jeunes individus sans facteur déclenchant apparent, la recherche d’états thrombophiliques sous-jacents est indispensable. L’hyperhomocystéinémie constitue un facteur de risque métabolique réversible, souvent négligé, contribuant à la thrombogenèse. Nous rapportons le cas d’un homme de 31 ans, électricien, présentant une dyspnée aiguë, une douleur thoracique pleurétique et une toux. L’évaluation clinique a révélé une tachypnée, une tachycardie et une hypoxémie. L’électrocardiogramme a montré une tachycardie sinusale avec un aspect S1Q3T3. L’analyse des gaz du sang artériel a mis en évidence une hypoxémie associée à une alcalose respiratoire. L’angioscanner thoracique a confirmé la présence d’un thrombus important dans l’artère pulmonaire principale droite entraînant une obstruction luminale supérieure à 50 %. L’échocardiographie a révélé une souffrance cardiaque droite. Le bilan de thrombophilie de routine était négatif ; cependant, une hyperhomocystéinémie marquée (>65 μmol/L) associée à un faible taux de folates et à des taux limites de vitamine B12 a été observée. Le patient a été traité par anticoagulation et supplémentation vitaminique, avec une amélioration clinique notable. Ce cas met en évidence l’hyperhomocystéinémie comme une cause réversible mais sous-reconnue d’EP non provoquée. Une détection précoce et une correction adaptée peuvent réduire significativement le risque de récidive et améliorer le pronostic.
Memory CD8+ T cells are central to multiple sclerosis (MS) and undergo clonal expansion, but disease-associated states remain incompletely defined. By single-cell profiling of circulating memory CD8+ T cells from patients with relapsing-remitting MS, healthy volunteers, and neuroinflammatory controls, we identified an MS-associated cytotoxic subset with NK-like features. These cells increase around relapse activity and belong to an oligoclonal reservoir. In an independent cohort sampled at the first clinical event, an elevated frequency of NK-like CD8+ T cells predicted an aggressive MS course two years later and was associated with a migratory/inflammatory program. Bulk and single-cell RNA-seq confirmed the NK-like transcriptional signature, and functional assays demonstrated TCR-independent cytotoxicity. Immunostaining and spatial transcriptomics revealed enrichment of these cells in MS lesions and a spatial association with macrophages/microglia. Together, our results identify a cytotoxic NK-like CD8+ T-cell subset that links peripheral inflammation to CNS lesions and may serve as an early biomarker of MS severity.
The increasing global burden of cancer necessitates innovative therapeutic strategies. Cell therapy represents a major breakthrough in oncology, evolving rapidly from the successful application of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies to a multiplatform landscape characterized by the concurrent development of diverse strategies. Current research focuses on T cell receptor-engineered T (TCR-T) cells, tumor-infiltrating lymphocytes (TILs), gamma delta (γδ) T cells, CAR-natural killer (CAR-NK) cells, CAR-macrophages (CAR-Ms), and various strategies based on dendritic cells (DCs), B cells, and stem cells. The translational paradigm is expanding from the relatively mature field of hematologic malignancies to the more prevalent and mechanistically complex domain of solid tumors. In recent years, this field has exhibited a clear trend toward expansion from autologous therapies to allogeneic "off-the-shelf" platforms. Approaches such as CAR-NK and CAR-natural killer T (CAR-NKT) cell therapies exhibit significant clinical potential because of their low immunogenicity and reduced risk of graft-versus-host disease (GvHD). Concurrently, in vivo engineering technologies that directly deliver CAR genes in situ are emerging as promising approaches to lower costs and simplify manufacturing by bypassing complex ex vivo procedures. This review systematically outlines recent advances in these strategies, focusing on their mechanisms of action, target antigens, and clinical translation. Despite progress, formidable challenges remain, including tumor heterogeneity, the immunosuppressive tumor microenvironment (TME), and therapy-related toxicity. To address these challenges, future research will focus on novel target discovery, enhanced toxicity management, and scalable manufacturing processes. The integration of multidisciplinary technologies, such as multiomics analysis, artificial intelligence, and synthetic biology, will advance cell therapies toward safer, more effective, and widely accessible applications.
X-linked hypophosphatemia (XLH) is a rare hereditary disorder characterized by PHEX gene mutations, elevated FGF23 levels, and impaired bone mineralization. Burosumab, a monoclonal antibody targeting FGF23, has demonstrated clinical efficacy; however, the immunological dynamics during treatment remain unexplored. This study employed longitudinal single-cell RNA sequencing (scRNA-seq) to characterize peripheral blood immune cell alterations across multiple treatment stages in pediatric XLH. We performed scRNA-seq on peripheral blood mononuclear cells from pediatric patients with XLH at five time points spanning pretreatment and burosumab therapy phases, along with healthy pediatric controls. A total of 93,112 cells were analyzed using comprehensive bioinformatic pipelines, including unsupervised clustering, pseudotime trajectory analysis, temporal gene expression profiling, and cell-cell communication inference. Eleven major immune cell populations were identified, with notable dynamic alterations in T cells and natural killer (NK) cell subtypes across treatment stages. The cellular proportion of T helper 2 (Th2) cells and regulatory T (Treg) cells were elevated before treatment and normalized during therapy, whereas T helper 17 (Th17) cells exhibited reciprocal patterns. Genes upregulated in Treg cells during early treatment were enriched in osteoclast differentiation pathway. Natural killer subtype 2 cells showed enrichment in osteoclast differentiation and interleukin-12 response pathways. Cell-cell communication analysis identified dynamic interactions among Th2 cells, Th17 cells, Treg cells, and NK cell subtypes mediated by KLRB1-CLEC2D and SELL-SELPLG ligand-receptor pairs. This longitudinal transcriptomic study provides the first comprehensive characterization of peripheral immune dynamics during burosumab therapy in XLH, offering new insights into the immunological mechanisms underlying treatment response.
The role of heritable genetic variation in hematologic traits in adults is well established, yet the genetic architecture of neonatal blood cell traits is unknown. Leveraging flow cytometry profiling in cord blood samples from 382 Hispanic newborns, we conducted genome-wide association studies (GWASs) of 24 blood cell phenotypes to assess the impact of genetic and birth-related characteristics. We identified six genome-wide significant loci, including a signal at chromosome 2p11.2 spanning CD8A and CD8B that was associated with CD4+CD8+ double-positive T cells (rs35505884-C: p = 6.83 × 10-26). The lead variant showed strongly differentiated allele frequencies between European (22.1%) and admixed American (11.8%) populations and was associated with global (p = 2.51 × 10-6) and local (p = 2.01 × 10-8) Indigenous American ancestry. Colocalization with single-cell expression quantitative trait loci (eQTLs) revealed convergence of GWAS effects with regulation of CD8A expression in natural killer cells and CD4+ effector memory T cells with posterior probability (PPH4) >0.85. A locus at 6p21.33 was associated with CD4-CD8+ cytotoxic T cells (rs2853973-C, p = 3.90 × 10-8) and colocalized with MICA-AS1 expression across multiple immune cell types (PPH4 > 0.85). Additional nominal genome-wide significant loci were detected for total CD45+ lymphocytes, CD19+CD56+CD16+ natural killer cells, and CD4+CD8- helper T cells. C-section delivery and biological sex significantly altered blood cell profiles, with the largest magnitudes of association observed between C-section and total CD3+ T cells (β = 0.39) and CD4+ helper T cells (β = 0.39), and between female sex and CD4+CD8- (β = 0.39) and CD4-CD8+ T cells (β = -0.36). Our study demonstrates that blood cell composition at birth is under strong genetic regulation in Hispanic newborns, highlighting the value of studying complex traits in early life.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide despite recent advances in systemic therapy. The introduction of immune checkpoint inhibitors has substantially expanded treatment options for advanced disease; however, durable responses are observed only in a subset of patients. Increasing evidence indicates that this limited efficacy is largely driven by the complex immune landscape of HCC, which is shaped by disease aetiology, tumour microenvironment-mediated immune suppression, and impaired innate immune surveillance. Chronic viral hepatitis and metabolically driven liver diseases represent the principal drivers of HCC and profoundly influence immune regulation within the liver. Persistent antigen exposure, metabolic reprogramming, and stromal remodelling contribute to dysfunctional T- and natural killer (NK) cell responses, while immunosuppressive components of the tumour microenvironment, including tumour-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and inhibitory ligands such as HLA-G, facilitate immune escape and therapeutic resistance. In this review, we discuss recent advances in HCC immunotherapy, focusing on emerging checkpoint pathways such as TIGIT and Tim-3, glypican-3 targeted cellular therapies and bispecific antibodies, and NK cell-based therapeutic strategies. We further highlight the role of liquid biopsy approaches for treatment monitoring and biomarker development. Together, these insights emphasize the need for biomarker-guided patient stratification and integrated therapeutic strategies to improve the clinical efficacy of immunotherapy in HCC. Liver cancer, particularly hepatocellular carcinoma (HCC), is one of the leading causes of cancer‐related deaths worldwide. Although new immunotherapies have improved treatment options, they only work well for some patients. This is because liver tumours develop in a complex immune environment that often suppresses the body’s natural ability to fight cancer. Chronic liver diseases, such as viral hepatitis and fatty liver disease, further weaken immune responses and help tumours evade detection. This review explains how these immune changes influence treatment outcomes and highlights promising new immunotherapies, including therapies that target immune checkpoints, engineered immune cells, and natural killer cells. It also discusses the growing role of blood‐based biomarkers to help identify which patients are most likely to benefit from these treatments, with the goal of advancing more personalized and effective care for liver cancer.
Acupuncture and moxibustion are evidence - based modalities derived from traditional Chinese medicine. They employ strategic needle insertion or moxa - derived thermal stimulation at specific acupoints to ameliorate pathological conditions. Robust clinical data have validated their efficacy in mitigating gastrointestinal dysfunction, chemotherapy - induced neuropathy, cancer - related fatigue, and radiation - induced xerostomia. Crucially, within immunosuppressive tumor microenvironments (TME), these interventions exert direct antitumor effects through multimodal immunomodulation (1): Potentiation of innate immunity via enhanced cytotoxicity of natural killer (NK) cells, polarization of macrophages toward the proinflammatory M1 phenotype, regulation of microglial function, and modulation of mast cell (MC) degranulation; (2) Reprogramming of adaptive immunity through restoration of the T helper 1 (Th1)/T helper 2 (Th2) balance and activation of cluster of differentiation 8 - positive (CD8+) T cells; (3) Remodeling of the TME by attenuating immunosuppressive networks (e.g., regulatory T cells ((Tregs), myeloid - derived suppressor cells ((MDSCs)) while enhancing effector cell infiltration. This review synthesizes mechanistic advances that demonstrate how acupuncture and moxibustion rebalance antitumor immunosurveillance, thereby positioning them as promising adjuvant modalities in integrative oncology.
Alzheimer's disease (AD) and sleep deprivation (SD), two common conditions in the elderly, share complex molecular connections and may mutually influence each other's pathogenesis. Current drugs only relieve symptoms with limited efficacy, making it urgent to explore the shared pathological mechanisms and potential intervention targets of the two conditions. This study used bioinformatics: first screening AD-related genes associated with SD and N4-acetylcytidine (ac4C) from relevant data; then identifying key genes via Mendelian randomization (MR) analysis and machine learning; finally screening AD-related key cells with single-cell RNA sequencing (scRNA-seq) data, to provide a basis for revealing the molecular and cellular regulatory mechanisms of AD-SD comorbidity. This study integrated bulk RNA sequencing (RNA-Seq) and scRNA-seq data from the Gene Expression Omnibus (GEO) database to identify AD-related key genes associated with SD and ac4C. Machine learning algorithms, including MR, were applied to screen these key genes. Additionally, gene set enrichment analysis (GSEA) was conducted to explore the pathways associated with the key genes, while ssGSEA was used to assess differences in immune cell infiltration. For the scRNA-seq data, key cells involved in AD pathology were further identified. Subsequently, the differential expression of the two key genes was validated using peripheral blood samples collected from AD and SD patients. Through MR analysis, machine learning algorithms, and other analytical approaches, FLOT1 and EEF1D were identified as key genes. GSEA revealed that these key genes were enriched in multiple pathways, including the lysosome pathway, chemokine signaling pathway, and leukocyte transendothelial migration. Immune cell infiltration analysis suggested that myeloid-derived suppressor cells (MDSCs) might serve as key immune cells. Additionally, scRNA-seq analysis identified microglia, CD4 + T cells, CD8 + T cells, and natural killer (NK) cells as key cell types involved in AD pathogenesis. Critically, these key genes were successfully validated in peripheral blood samples from AD and SD patients, aligning with the above analysis. Overall, FLOT1 and EEF1D were identified as key genes associated with SD and ac4C in AD. This finding provided new grounds for the clinical diagnosis and treatment of AD.
Chikungunya virus (CHIKV) infection causes acute febrile illness and debilitating arthralgia, with up to 40-80% of patients developing chronic chikungunya disease characterized by persistent arthralgia and fatigue lasting months to years. The immunological mechanisms underlying this transition remain poorly understood. We performed longitudinal immune profiling of CHIKV-infected patients stratified by clinical outcome. Single-cell RNA sequencing of peripheral blood mononuclear cells collected during acute infection and six months post-infection was combined with multiplex plasma cytokine and flow cytometric analysis. Patients who later developed chronic symptoms were characterized by early innate immune hypoactivation during acute infection, characterized by reduced monocyte and dendritic cell frequencies, lower circulating IFN-α, IL-6 and IL-8, and reduced antigen-presentation and interferon-associated transcriptional programs. This was accompanied by diminished adaptive immune activation, including reduced IL-17 and IL-21 and lower HLA-DR expression across multiple T-cell subsets. Cell-cell communication analysis further indicated impaired acute monocyte-centered immune coordination in chronic progressors, whereas non-chronic patients displayed stronger monocyte-driven innate-to-adaptive signaling. By six months, chronic patients showed persistent innate remodeling, including increased non-classical monocytes, altered plasmacytoid dendritic cell and natural killer cell transcriptional programs, elevated CXCL10, reduced IL-6 and MMP8, and emergence of NK-centered predicted communication networks. Longitudinal transcriptomic analysis further identified divergent immune recovery trajectories, most prominently in non-classical monocytes and plasmacytoid dendritic cells. Together, these findings suggest that chronic chikungunya disease is associated with early innate immune hypoactivation followed by persistent innate immune remodeling, providing insight into immune mechanisms that may contribute to post-viral chronic inflammatory syndromes.
Combined immunodeficiencies (CIDs) are a severe class of inborn errors of immunity characterized by defective T cell development and function, often accompanied by impaired humoral and natural killer (NK) cell responses. Despite their shared clinical classification, the immunological heterogeneity within CIDs remains incompletely understood. This study aims to characterize the immune cell landscape in CID patients caused by disease-causing mutations in different genes to identify immunophenotypic patterns. We analyzed peripheral blood immune cells from four CID patients with disease-causing mutations in ARPC1B, EZR, BCL10, and IRF4 using mass cytometry. Unbiased computational approaches were used to profile major immune populations and their subsets, and results were compared with healthy control samples to identify differences in immune cell frequencies and phenotypes. All patients retained major immune populations, but their relative frequencies differed significantly from those of healthy controls. Patients with EZR and ARPC1B deficiency had markedly reduced CD4+ and CD8+ T cell frequencies, whereas the BCL10-deficient patient had a near absence of NK cells, highlighting mutation-specific immune distributions. Detailed T cell subset analyses revealed increased naïve and decreased memory T cells in patients with BCL10 and IRF4 deficiencies, indicative of impaired T cell activation and memory formation. In contrast, ARPC1B deficiency was associated with elevated memory T cells and reduced naïve cells, suggesting thymic output defects. The Ezrin-deficient patient maintained a naïve-to-memory T cell ratio similar to controls despite an overall reduction in T cells. B cell abnormalities were consistent across patients, characterized by increased naïve B cells, decreased memory B cells, and severely diminished plasmablast frequencies. Our findings reveal pronounced immunological heterogeneity among CID patients caused by different genetic defects, challenging the notion that CIDs constitute a uniform entity. Disease-causing gene-specific alterations in immune cell composition and differentiation states underscore the complexity of CID pathophysiology. Comprehensive immunophenotypic profiling offers valuable insights into distinct mechanistic pathways and may guide the development of tailored therapeutic strategies to improve clinical outcomes for CID patients.