Natural killer (NK) cells, known for their potent anti-tumor activity, have faced challenges in clinical trials due to limited methods to enhance their expansion and anti-tumor potential. This review highlights the unique characteristics of osteoclasts-expanded supercharged NK (sNK) cells, showcasing their suitability for clinical applications. sNK cells exhibit remarkable anti-tumor efficacy, prolonged survival, and increased expansion when cultured with osteoclasts and probiotic bacteria. A comparative analysis with other NK cell expansion techniques reveals the distinct advantages of sNK cells in terms of survival, expansion, and functionality. Through proteomic, transcriptomic, single-cell RNAseq, and functional assessments, sNK cells demonstrate the ability to target both poorly differentiated/stem-like tumors and well-differentiated tumors. Moreover, they can supplement the functional deficiency of autologous NK cells, restoring their effectiveness in combating cancer. The exceptional attributes of sNK cells position them as a unique and promising candidate for inclusion in clinical trials for cancer patients.

Natural killer (NK) cells play critical roles in innate immunity and in shaping adaptive immune responses. Recent studies reveal their dual role in autoimmunity, either with a protective role by eliminating autoreactive cells or as contributors to pathogenic inflammation. This review summarizes current understanding of NK cell biology in endocrine autoimmune diseases, focusing on what is known for type 1 diabetes and autoimmune adrenal failure-Addison's disease. We further discuss emerging therapeutic approaches focusing on cytokine-activated (supercharged) NK cells and CAR NK cells, and highlight knowledge gaps and future priorities.

Current therapeutic strategies for inflammatory bowel disease often rely on systemic immunosuppression or single-target biologics, which can lead to significant side effects or incomplete remission. To overcome this therapeutic hurdle, we recently proposed engineering dendritic cells (DCs) to de novo synthesize high concentrations of the active vitamin D (1,25[OH]2D) and A (retinoic acid or RA) because 1,25(OH)2D directly stimulates the expression of Foxp3 (the master regulator of CD4+ Tregs) and RA induces gut-homing receptor expression. In our previous studies, we engineered mouse DCs using a lentiviral vector to overexpress CYP27B1 (encoding 1α-hydroxylase) and ALDH1A2 (encoding RALDH2) to synthesize 1,25(OH)2D and RA, respectively. The engineered DCs stimulated CD4+Foxp3+ Tregs expressing CCR9 (a gut-homing receptor) both in vitro and in vivo. In addition, the engineered DCs robustly suppressed experimental colitis, a process that depended on CD4+Foxp3+ Tregs. In addition, the engineered DCs did not cause hypercalcemia, the major side effect associated with systemically high 1,25(OH)2D concentrations, suggesting a safety profile. Moreover, the engineered DCs upregulated tissue expression of CYP27B1 and ALDH1A2 genes for thirty days of the observational period. To evaluate the potential clinical translation of the engineered DCs, this study extended our previous animal studies to humans. Our data demonstrated that engineered human DCs, like their mouse counterparts, stimulated CCR9+CD4+Foxp3+ Tregs. Notably, our human data revealed that the engineered human DCs also stimulated α4β7+ and α4β7+CCR9+ CD4+Foxp3+ Tregs, a finding validated in vivo in mice. This finding is clinically significant because CCR9 mediates homing to the small intestine, while a4b7 targets both the small and large intestines, thereby offering "pan-intestinal" therapeutic coverage. Our human data thus further support the engineered DCs as a promising therapy for inflammatory bowel disease. Additionally, because CCR9 is a homing receptor for inflammation, the engineered DCs can potentially be a solution for a broad range of inflammatory diseases.

Aggressive tumors are treated with surgery, radiation, chemotherapy, targeted therapy, and various immunotherapies. Cancer immunotherapies under investigation encompass monoclonal antibodies, including checkpoint inhibitors, bispecific antibodies, and T cell redirecting antibodies, as well as gene-modified cell therapies such as CAR-T cells, donor lymphocyte infusions (DLI), antigen-specific DLI, and TCR-engineered T cells. While dendritic cell (DC)-based vaccines derived from peripheral blood have shown promise in preclinical studies, clinical trials have been less effective. Recently, a novel allogeneic DC vaccine has been developed using CD34+ hematopoietic stem cells (HSCs), which are engineered to overexpress CD93, CD40 ligand (CD40L), and CXCL13, thereby enhancing immune activation and improving scalability and effectiveness. This approach has shown potential in controlling tumor growth by stimulating the immune system in preclinical studies. This commentary highlights the promise of engineered allogeneic DC vaccines, their benefits over autologous methods, and the challenges of clinical translation. Combining this DC vaccine with checkpoint inhibitors and refining its design could make it a game-changing off-the-shelf cancer therapy.

This study was conducted to investigate whether natural killer (NK) cells can kill and/or inhibit the tumor growth of hematological tumors. When K562, the chronic myeloid leukemia cell line, was treated with the culture media collected from interleukin-2 (IL-2) and anti-CD16 mAbs-treated NK cells, increased surface expression levels of differentiation antigens MHC-class I, CD54, and PD-L1 were observed on K562. This finding validated our previous reports demonstrating that the NK cells induce tumor differentiation via their secreted factors. Next, we investigated NK cell-mediated cytotoxicity against stem-like and differentiated K562, and observed that increased NK cells induced direct cytotoxicity in stem-like K562 compared with differentiated K562. Upon differentiation, tumors become resistant to direct NK cell-mediated cytotoxicity, but were lysed by NK cells via antibody-dependent cellular cytotoxicity (ADCC). NK cell-mediated ADCC was observed when K562 cells were treated with anti-PD-L1. Thus, primary NK cells, although they cannot induce direct lysis in differentiated tumors, can target them via ADCC.

This study delves into effective therapeutic strategies for endometrial cancer, focusing on the distinct functions of primary NK cells and supercharged NK (sNK) cells in targeting endometrial tumors. The research utilized AN3CA and HEC1B tumors to highlight the differences in efficacy between the two cell types. Notably, sNK cells exhibited the ability to target both stem-like AN3CA and well-differentiated HEC-1B tumors, while primary NK cells targeted the stem-like tumors exclusively. To demonstrate the in vivo effectiveness of sNK cells, AN3CA tumors were implanted in the uterus of humanized-BLT (hu-BLT) mice, followed by sNK cell therapy. The results showed that a single infusion of sNK cells significantly reduced tumor burden and restored immune cell function in the hu-BLT mice. This outcome underscores the potential of sNK therapy in eliminating stem-like, poorly differentiated, and well-differentiated tumors, while also enhancing the function of endogenous NK cells to better manage remaining tumors in patients. The findings of this study suggest that innovative treatments like sNK cell therapy represent the future of uterine cancer treatment, offering new avenues for effectively addressing the complexity of this disease.

Natural killer (NK) cells are long known for their anti-cancer function; however, their use in clinical trials has not been well-positioned yet due to the lack of reliable methods to augment their expansion and anti-tumor potential. In our previous publications, we have demonstrated the methodology to enhance the number and function of NK cells by co-culturing peripheral blood-derived NK cells with osteoclasts (OCs) and sonicated probiotic bacteria (sAJ2). Due to significantly increased potency, these NK cells were named supercharged NK (sNK) cells. sNK cells have significantly high anti-tumor activity as well as increased cell proliferation and survival. In the current study, we present data to support the evidence that sNK cells specifically target cancer cells and not primary immune cells. We also demonstrate that sNK cells circulated to humanized-BLT (hu-BLT) mice tissues when mice were adoptively transferred, and resulted in no toxicity or visible adverse effects. However, they increased the percentages of NK cells in the peripheral blood of the mice, which may contribute to restoring the functional loss of autologous NK cells, allowing the patient's NK cells to become functional. These attributes of sNK cells make these cells not only a unique population of NK cells but also cells that can effectively be used in clinical trials of cancer patients. Overall, the data shown in this study suggest that sNK cells have potential for clinical trial applications.

Natural killer (NK) cells play a key role in targeting cancer, virus-infected, and senescent cells through direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). Monitoring NK cell cytotoxicity is crucial for evaluating immune function, tracking disease progression, and assessing therapeutic outcomes, particularly in oncology and immunology. NK cells help manage infections, cancer, and other health conditions through their cytotoxic actions. Changes in NK activity can signal disease states or responses to treatments. NK cell-based therapies require functional assessments to maximize effectiveness. Abnormal NK cytotoxicity may be linked to autoimmune diseases or immune exhaustion in tumor microenvironments. Various methods are used to measure NK cell cytotoxicity, with the chromium-51 release assay once being the gold standard by detecting radioactive chromium release upon target cell destruction. This report highlights the significant potential of a label-free impedance-based Real Time Cell Analysis (RTCA) platform with complementary live cell imaging capability for label-free, dynamic monitoring of NK-target cell interactions over time.

Despite major advances in antiretroviral therapy (ART), a definitive cure for human immunodeficiency virus (HIV) remains elusive. This review aims to propose a unified, multidimensional framework for HIV cure that integrates virologic, immunologic, and clinical perspectives to guide future research and therapeutic strategies. A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant literature on HIV cure research. Articles published primarily between 2008 and 2026 were screened based on relevance, scientific rigor, and contribution to key themes. Findings were synthesized qualitatively to provide an integrated overview of emerging concepts, persistent challenges, and future directions in HIV cure research. Effective HIV cure strategies must integrate three interconnected dimensions: (1) virologic cure through durable suppression or elimination of replication-competent virus, (2) clinical cure through sustained remission without antiretroviral therapy (ART), and (3) immunologic cure through restoration of functional immune competence and inflammatory homeostasis. Current and emerging approaches, including latency-targeting agents, broadly neutralizing antibodies, therapeutic vaccines, immune modulators, and gene-editing technologies, demonstrate potential to bridge viral suppression with immune-mediated control. However, critical challenges persist, including reservoir heterogeneity, immune senescence, viral diversity, and the absence of standardized immunologic metrics. Proposed endpoints extend beyond CD4+ T cell counts to functional T cell responses, immune memory restoration, and normalization of inflammatory profiles. An effective HIV cure must integrate viral suppression, immune restoration, and functional remission. This unified, multidimensional framework provides a foundation for next-generation therapeutic strategies and clinical trial design aimed at achieving durable, host-mediated control.

Gallbladder cancer (GBC) is a prevalent and aggressive malignancy of the biliary system. Studies have revealed that Proteasome 26S subunit ATPase 2 (PSMC2) is overexpressed and associated with the development process of several cancers. However, the specific role in GBC remains unknown. This study aims to explore the association between PSMC2 and GBC pathogenesis. We assessed PSMC2 expression from normal and GBC patient samples. Using Cell Counting Kit-8 (CCK-8), colony formation, scratch, and Transwell migration assays, we investigated the effects of PSMC2 on the proliferation and migration of GBC cells. Subsequently, through bioinformatics analysis, we identified the cell cycle pathways related to PSMC2 in GBC cells. Using flow cytometry, we identified that knocking down PSMC2 could alter the cell cycle in GBC cells. Then, through bioinformatics analysis and Western blot assay, we discovered the relationship between the AKT/Cyclin D1/CDK6 pathway and the cell cycle and used an RAC-alpha serine/threonine-protein kinase (AKT) inhibitor and an Cyclin-Dependent Kinase 6 (CDK6) inhibitor to restore the GBC cell proliferation induced by PSMC2 overexpression in order to detect the mechanism of PSMC2's role in GBC. We found that PSMC2 was observably upregulated in GBC patient samples. In vitro experiments demonstrated that knocking down PSMC2 significantly suppressed the GBC cells' proliferation and migration abilities. Bioinformatics assays showed a significant enrichment of the cell cycle pathway in both the GO and KEGG databases. Furthermore, cell cycle-related genes CDK6 and Cyclin D1 were significantly upregulated in PSMC2-high expressed clusters. Then we identified that knockdown of PSMC2 could suppress AKT activation and reduce the expression of Cyclin D1 and CDK6. Moreover, treatment with the AKT inhibitor could restore the upregulated CDK6 expression after PSMC2 overexpression, and treatment with the CDK6 inhibitor restored the progression and altered the cell cycle distribution in GBC cells induced by PSMC2 overexpression. PSMC2 was significantly upregulated in GBC tissues and cell lines. PSMC2 expression promotes progression and migration in GBC cells, potentially through regulation of the AKT/Cyclin D1/CDK6 signaling pathway.

Chronic hepatitis B (CHB) infection leads to progressive dysfunction and exhaustion of antiviral immune cells, which is a primary obstacle to clinical cure. Although the phenotypic hallmarks of exhausted T cells are well described, the hierarchical trajectory, subset-specific heterogeneity, and underlying mechanisms of exhaustion across the full spectrum of immune cells in the unique hepatic microenvironment remain poorly defined. This review provides a comprehensive and critical synthesis of recent advances in immune exhaustion during CHB. We delineate the common and distinct exhaustion programs among T, B, and natural killer cells, highlighting the pivotal roles of transcription factors and metabolic dysregulation. Furthermore, we critically evaluate the limitations of current evidence and pinpoint critical knowledge gaps, such as the heterogeneity of non-classical exhausted subsets and the liver-resident immune compartment. By framing these findings within a critical and comparative context, this review not only updates our understanding of immune exhaustion but also proposes a roadmap for developing more precise immunotherapies aimed at achieving a functional cure for CHB.

B lymphocytes, which originally develop in the bone marrow, are key components of humoral immunity and are responsible for antibody production. B lymphocytes arise from progenitor B cells (pro-B cells), which are located in the fetal liver during early development and are generated predominantly in the bone marrow before birth. Based on their stage of maturation and function, B cells are divided into many subsets. B cells play a critical role in the humoral immune response through antibody secretion; however, accumulating evidence indicates that B cells also have more diverse functions in the immune system. Different B cell subsets can modulate effector T-cell responses through antigen presentation, costimulation, and cytokine production. A distinct subpopulation of B cells, termed regulatory B cells (Bregs), negatively regulates cellular immune responses and contributes to the control of inflammation, infectious diseases, autoimmunity, and cancer. These cells may represent viable targets for therapeutic manipulation or immunomodulation independent of antibody production. In this review, we discuss the various B cell subsets and describe non-humoral functions of B cells, with particular emphasis on regulatory B cells and their roles in immunological diseases and cancer.

Type I interferons (IFN-I) exert a significant influence on the immune system. Produced by certain immune cells, they affect other immune cells and mediate diverse effects, including antiviral activity, inhibition of tumor growth, and suppression of cell proliferation. IFN-I is also implicated in the development and persistence of autoimmune disorders. Research has shown that abnormal IFN-I levels and IFN-I-regulated gene expression in the blood or tissues of individuals with autoimmune diseases are associated with disease onset, clinical manifestations, and severity. Monogenic conditions known as Type I interferonopathies-caused by mutations affecting the IFN-I signaling pathway-share clinical features with systemic lupus erythematosus (SLE). Both preclinical models and clinical trials targeting the IFN-I signaling pathway have yielded promising results for the treatment of autoimmune diseases. This review provides an overview of the interplay between epigenetics, various types of RNAs, transcription factors, and IFN-I. It discusses epigenetic modifications and transcription factor dysregulation, offering insights into disease mechanisms and potential future therapeutic advancements.

The aim of this study is to identify and validate ketogenesis-immune cross-talk genes with prognostic significance in LUAD patients. Bulk RNA-seq data of LUAD were obtained from TCGA and GEO databases to analyze differentially expressed genes (DEGs), which were intersected with ketogenesis-related gene sets from MSigDB. DEGs associated with anti-PD-1 therapy sensitivity were further identified. Univariate and multivariate Cox regression analyses were performed to determine independent prognostic genes. Molecular subtypes and an 8-gene ketogenesis-immune prognostic signature were constructed and validated. Single-cell RNA-seq data were used to map cell-type-specific expression of prognostic genes. Functional effects of SLC2A1, a key metabolic regulator, were evaluated in A549 cells using overexpression/knockdown approaches combined with β-hydroxybutyrate (BHB) treatment. A total of 135 ketogenesis-immune cross-talk genes were identified. Consensus clustering defined two LUAD subtypes with distinct prognosis and immune landscapes. Single-cell analysis revealed SLC2A1 enrichment in epithelial tumor cells. Functional assays showed that SLC2A1 overexpression enhanced proliferation, migration, glycolysis, and ATP production, whereas knockdown suppressed these processes; BHB partially rescued energy deficits in SLC2A1-deficient cells. Mechanistically, SLC2A1 regulated ketone-body utilization and AMPK/mTOR signaling, linking metabolic reprogramming with tumor growth and immune modulation. SLC2A1 is a critical regulator of ketone-body metabolism in LUAD and serves as a potential prognostic factor.