Melanoma is one of a small number of cancers where there is a clear role for surgery in selected patients with metastatic disease. However, the role of surgery for metastatic melanoma in the age of immune checkpoint blockade is not clearly delineated. Adoptive cell therapies, which include tumor-infiltrating lymphocytes and chimeric antigen receptor T cells, often require metastasectomy to obtain the tumor-specific immune cells and/or antigens necessary to create personalized cell-based products. It is, therefore, essential that the surgeon be well-versed in techniques for procuring appropriate tissue and familiar with their delivery to ensure appropriate preoperative planning and postoperative recovery.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Immunological memory is a hallmark of the adaptive immune system. However, considerable evidence indicates that the natural killer (NK) cell subset of innate lymphoid cells also mediates specific memory responses to diverse antigens, including peptides. Even though the existence of NK cell memory is established, the mechanism behind NK cell adaptive responses is yet to be elucidated. Previously, we observed that the Ly49 family of class-I MHC receptors in mice are critical for the formation of adaptive NK cell memory responses. To define the nature of Ly49 involvement in NK cell memory responses, we investigated the contribution of individual Ly49 receptors and their defined class-I MHC ligands. We determined that the Ly49 requirement for the generation of NK memory responses is not uniform. Specifically, Ly49C and/or Ly49I proteins are indispensable for the adaptive NK cell responses as assessed by contact hypersensitivity recall responses to haptens and peptides, in H-2b and H-2d MHC backgrounds. In contrast, the highly expressed inhibitory receptor, Ly49G, did not appear to play any role in NK cell memory responses as determined using antibody-mediated subset depletion and gene-deficient mouse models, even in strains containing known ligands for Ly49G. These findings point to a unique role for Ly49C/I in adaptive NK cell antigen recognition and provide further insight into the mechanism behind adaptive NK cell responses.

The skin is the primary barrier against environmental insults, safeguarding the body from mechanical, chemical and pathogenic threats. The frequent exposure of the skin to environmental challenges requires an immune response that incorporates a sophisticated combination of defenses. Tissue-resident lymphocytes are pivotal for skin immunity, working in tandem with commensal bacteria to maintain immune surveillance and homeostasis, as well as participating in the pathogenesis of several skin diseases. Indeed, it has been estimated that the human skin harbors nearly twice as many T cells as found in the circulation. Effective treatment of skin diseases and new therapy development require a thorough understanding of the complex interactions among skin tissue, immune cells and the microbiota, which together regulate the skin's immune balance. This Review explores the latest developments and understanding of this critical barrier organ, with a specific focus on the role of skin-resident T cells.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.

The purpose of this study was to explore the genetic characteristics and immune cell infiltration related to intervertebral disc degeneration through multidataset analysis, predict potential therapeutic drugs, and provide a theoretical basis for clinical treatment. The gene expression profile data of the GSE70362, GSE186542, and GSE245147 datasets were downloaded from the Gene Expression Omnibus (GEO) database, and the hub genes were identified through differentially expressed gene analysis, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) functional annotation and Mendelian randomization analysis were performed. Hub genes and immune cells were identified. Infiltration status was determined through GSEA and GSVA to clarify the specific signalling pathways associated with key genes and explore the potential molecular mechanisms by which key genes affect disease progression. The key genes were reversely predicted using miRNA grid construction and transcription factor regulation, and genes related to disease regulation were obtained from the GeneCards database. Finally, the differentially expressed genes were used for drug prediction through the Connectivity Map database to identify potential drugs for the treatment of intervertebral disc degeneration. The feasibility of the predicted drugs was tested by molecular docking technology. Real-time quantitative PCR was used to confirm the expression of key genes in the tissue samples.A total of 126 differentially expressed genes were identified in the GEO database, and 4 differentially expressed hub genes (COL6A2, DCXR, GLRX, and PDGFRB) were identified through bioinformatics methods. Immune infiltration analysis revealed that NK cells, macrophages, and eosinophils were activated during IVDD, whereas mast cells and T cells were suppressed. GO and KEGG analyses revealed that key genes are involved in the development of this disease through signalling pathways such as the glycolysis pathway, the oxidative phosphorylation pathway, the cholesterol regulatory pathway, and the haem metabolism pathway. Analysis of the constructed miRNA grid revealed that key genes are jointly regulated by multiple transcription factors, among which the most important motif is cisbp_M5578. Disease regulation-related genes were obtained through the GeneCards database, analysis of the correlation with key genes was performed, and the expression levels of the two mRNA and miRNA were significantly correlated. Finally, drug prediction performed through the Connectivity Map database revealed that drugs such as Abt-751, LY-2183240, podophyllotoxin, and vindesine can alleviate or even reverse the disease state. Finally, we collected 10 IVDD and 10 healthy disc tissue samples, and the RT‒qPCR results were consistent with the bioinformatics results. We identified COL6A2, DCXR, GLRX, and PDGFRB as key genes involved in IVDD. In addition, drugs such as Abt-751 are expected to control and reverse the progression of the disease. In the future, these key genes and predicted drugs may provide new directions for further mechanistic studies as well as new therapies for IVDD patients.

Multiple myeloma (MM) is a haematological malignancy originating from terminally differentiated B cells, resulting in significant morbidity and mortality. Currently, MM is regarded as an incurable disease, often exhibiting a relapse-remitting pattern that necessitates multiple lines of therapy. It is now well-established that ineffective immunosurveillance plays a critical role in the progression of MM. Consequently, strategies that redirect immune effector cells against MM have emerged as effective treatment modalities, particularly in cases where standard care therapies fail. T cell-based immunotherapy has gained considerable attention in ongoing clinical trials; however, natural killer (NK) cells, known for their ability to execute cytotoxicity against infected and malignant cells with precision, may offer complementary therapeutic advantages over T cells and possess untapped therapeutic potential. This review seeks to introduce readers to the significance of NK cell-mediated immunosurveillance in the context of MM, explore the potential benefits of redirecting NK cells against MM, and illustrate how current treatment strategies are often reliant on the functionality of NK cells. Most importantly, new promising mechanisms of harnessing NK cell-based immunity against MM are reviewed and put into a clinical perspective to highlight their implications for patient treatment and outcomes.

Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD.

This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics.

PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p < 0.0001).

This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

Natural killer (NK) cells are widely involved in the field of tumor immunotherapy due to their unique killing ability. However, the durability and efficacy of NK-cell monotherapy are facing great challenges owing to the limitation of immunosuppressive tumor microenvironment (TME). NK cell-derived exosomes (Neo) not only play an innate immunomodulatory role similar to NK cells but also emerge as promising antitumor nanocarriers. In this study, an engineered Neo (R@Neo-MN) was designed that encapsulates the multifunctional antitumor drug (Raddeanin a, RA) and modified with maleimide (Mal, M) and mannose (Man, N). The obtained R@Neo-MN could not only exert NK cell-like antitumor function but also induce the immunogenic cell death of tumors to release tumor-associated antigens (TAAs). Furthermore, R@Neo-MN activated the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) to release type I interferons (IFN). Then, R@Neo-MN could capture TAAs through Mal and specifically target dendritic cells (DCs) through Man, thereby promoting the maturation of DCs and enhancing tumor-specific cytotoxic T-cell (CTL)-mediated adaptive immunity. The released IFN further promoted the infiltration and activition of NK cells and CTLs at the tumor site. Our study suggested a novel strategy that harnesses both innate and adaptive immunity for enhanced tumor immunotherapy.

Poorly differentiated gastric cancer (PDGC) is characterized by high invasiveness, rapid progression, and poor prognosis for patients. Differentiation therapy has long been a promising approach by manipulating the differentiation state of tumor cells to inhibit tumor growth, offering fewer side effects. Decitabine (DAC), is known as an inhibitor of DNA methylation, thus reactivating the transcription of previously methylated silenced genes associated with differentiation to induce a more differentiated state. This study used the differentiation-inducing agents DAC to treat two PDGC cell lines, MKN45 and NUGC4, and explored the impact of DAC on cell proliferation and influence of their sensitivity to Natural Killer cells (NK cells) mediated cytotoxicity. The results demonstrated a significant reduction in cell proliferation, migration, and invasion without affecting cell viability after DAC treatment. Additionally, transcriptomic analysis revealed that DAC-treated PDGC cells upregulated multiple immune-related genes, including the gene encoding for tumor necrosis factor alpha (TNF-α). Co-culture study of NK cells and PDGC cells showed that DAC treatment enhanced the sensitivity of these cancer cells to NK cell-mediated cytotoxicity, and TNF-α played a crucial role in promoting NK cell cytotoxicity. Following the subcutaneous implantation of tumors in nude mice, DAC administration significantly inhibited the growth of PDGC tumors and induced the upregulation of differentiation related genes. In summary, DAC effectively reduces the malignant characteristics of the PDGC cells by promoting their transition towards a higher state of differentiation and enhancing their sensitivity to NK cell-mediated killing, providing new insights for the mechanisms of the antitumor effects of DAC.

Chondrosarcoma (CHS) is a rare bone cancer originating from chondrocytes, with high-grade cases associated with high mortality rates. However, the prognostic factors and therapeutic targets for CHS have not been studied.

Graded gene differential analysis was conducted on 97 CHS tissues to identify genes associated with CHS grading. Additionally, we performed GO and KEGG enrichment analyses of the differentially-expressed genes (DEGs), as well as GSEA analysis, differential expression analysis, survival analysis, and univariable and multifactorial COX analysis of paired-like homology structural domain transcription factor 1 (PITX1). Furthermore, our findings investigated the relationship between tumor-infiltrating immune cells (TICs) in CHS tumors using CIBERSORT to calculate proportions and differences. Our findings also explored the associations among gene expression patterns, survival prognosis, TICs, and immune checkpoints across various cancer types. Finally, immunohistochemical staining was carried out on self-collected clinical samples to assess PITX1 expression levels and correlate them with clinical information.

Gene differential expression analysis revealed a strong correlation between PITX1 expression and tumor grade. GO, KEGG enrichment, and GSEA analysis demonstrated the association of PITX1 with cell proliferation-related processes, such as cell cycle regulation and mitosis, and differentiation-related processes, such as RNA processing. PITX1 expression was associated with tumor stage and survival outcomes. Immunoassay indicated a positive correlation between PITX1 levels and TICs, immune checkpoints, and graded TICs. Pan-cancer analysis confirmed the differential expression of the PITX1 gene across multiple cancers, impacting survival prognosis, TIC patterns, and immune checkpoint regulation. Lastly, our 75 collection of clinical patient tissue samples exhibited varying levels of PITX1 expression across different cancer grades while also demonstrating a significant association with tumor differentiation and metastasis.

PITX1 is a novel biomarker for distinguishing between high-grade and low-grade CHS, serving as a prognostic indicator for patients with this condition and presenting a promising target for immunotherapy. These findings offer innovative insights into the treatment of CHS.

Myeloid malignancies include various types of cancers that arise from the abnormal development or proliferation of myeloid cells within the bone marrow. Chimeric antigen receptor (CAR) T cell treatments, which show great potential for B cell and plasma cell cancers, face major challenges when used for myeloid malignancies. CAR natural killer (NK) cell-based immunotherapy encounters several challenges in treating myeloid cancers, including (i) poor gene transfer efficiency and expansion platforms in vitro, (ii) limited proliferation and persistence in vivo, (iii) antigenic heterogeneity, and (iv) an immunosuppressive tumor microenvironment. Despite these hurdles, "off-the-shelf" CAR-NK treatments showed encouraging results, marked by enhanced proliferation, prolonged persistence, enhanced tumor infiltration, and improved adaptability. This review offers a summary of the biological traits and cellular sources of NK cells along with a discussion of contemporary CAR designs. Furthermore, it addresses the challenges observed in preclinical research and clinical trials related to CAR-NK cell therapy for myeloid cancers, suggesting enhancement strategies.

Acute-on-chronic liver failure (ACLF) is characterized by fast progression and high mortality, with systemic inflammation and immune paralysis as its key events. While natural killer (NK) cells are key innate immune cells, their unique function and subpopulation heterogeneity in ACLF have not been fully elucidated. This study aimed to investigate the characteristics of NK cell subsets in the peripheral blood of patients with ACLF and determine their roles in the inflammatory responses.

Circulating NK cells (14 751 cells) from patients with ACLF and healthy controls (HCs) were subjected to single-cell RNA sequencing (scRNA-seq). Clustering and annotation were used to identify the features of NK cell subsets and the characteristics of disease progression in ACLF.

Four NK cell subsets were obtained, including adaptive NK cells, mature NK cells, inflamed NK cells, and CD56bright NK cells. Compared with the HCs, the patients with ACLF had a significantly lower proportion of Mature NK cells and a higher proportion of Inflamed NK cells. Quasi-temporal analysis showed that Inflamed NK cells were highly enriched in the late quasi-temporal sequence, and genes related to pro-inflammatory were significantly up-regulated in Inflamed NK cells. In addition, scRNA-seq and flow cytometry confirmed that the expression level of cell migration inducing hyaluronidase 2 (CEMIP2) in NK cells progressively increased from the HC group to the ACLF survival group and then to the ACLF death group.

scRNA-seq reveals that Inflamed NK cell subsets are associated with ACLF progression and poor prognosis. CEMIP2 may be a molecular marker for ACLF progression.

Natural killer (NK) cells exhibit potent cytotoxic activity against various cancer cell types. Over the past five decades, numerous methodologies have been employed to elucidate the intricate molecular mechanisms underlying NK cell-mediated tumor control. While significant progress has been made in elucidating the interactions between NK cells and tumor cells, the regulatory factors governing NK cell-mediated tumor cell destruction are not yet fully understood. This includes the diverse array of tumor ligands recognized by NK cells and the mechanisms that NK cells employ to eliminate tumor cells.

In this study, we employed a genome-wide CRISPR/Cas9 screening approach in conjunction with functional cytotoxicity assays to delineate the pathways modulating the susceptibility of colon adenocarcinoma HCT-116 cells to NK cell-mediated cytotoxicity.

Analysis of guide RNA distribution in HCT-116 cells that survived co-incubation with NK cells identified ICAM-1 as a pivotal player in the NKp44-mediated immune synapse, with NKp44 serving as an activating receptor crucial for the elimination of HCT-116 tumor cells by NK cells. Furthermore, disruption of genes involved in the apoptosis or interferon (IFN)-γ signaling pathways conferred resistance to NK cell attack. We further dissected that NK cell-derived IFN-γ promotes mitochondrial apoptosis in vitro and exerts control over B16-F10 lung metastases in vivo.

Monitoring ICAM-1 levels on the surface of tumor cells or modulating its expression should be considered in the context of NK cell-based therapy. Furthermore, promoting FasL expression on the NK cell surface is reaffirmed as an important strategy to enhance NK cell-mediated tumor killing, offering an additional avenue for therapeutic optimization. Additionally, considering the diffusion properties of IFN-γ, our findings highlight the potential of leveraging NK cell-derived IFN-γ to enhance direct tumor cell killing and facilitate bystander effects via cytokine diffusion, warranting further investigation.

Killer Ig-like Receptors (KIRs) regulate immune responses, maintaining the balance between activation and inhibition of the immune system. KIRs are expressed on natural killer cells and some CD8 T cells and interact with HLA class I molecules, influencing various physiological and pathological processes. KIRs' polymorphism creates a variability in immune responses among individuals. KIRs are involved in autoimmune disorders, cancer, infections, neurological diseases, and other diseases. Specific combinations of KIRs and HLA are linked to several diseases' susceptibility, progression, and outcomes. In particular, the balance between inhibitory and activating KIRs can determine how the immune system responds to pathogens and tumors. An imbalance can lead to an excessive response, contributing to autoimmune diseases, or an inadequate response, allowing immune evasion by pathogens or cancer cells. The increasing number of studies on KIRs highlights their essential role as diagnostic and prognostic biomarkers and potential therapeutic targets. This review provides a comprehensive overview of the role of KIRs in all clinical conditions and diseases, listed alphabetically, where they are analyzed.

Children with recurrent/metastatic neuroblastoma (NB) have a dismal survival (<25%). Novel therapies are desperately needed. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed on NB. C021 is a selective oncolytic herpes simplex virus modified to overexpress human interleukin-21 (hIL-21), a cytokine that enhances natural killer (NK) cell cytotoxicity. In the current study, we successfully engineered ex-vivo-expanded NK cells to express a chimeric antigen receptor (CAR) against ROR1 using mRNA electroporation and investigated the efficacy of anti-ROR1-CAR-NK cells combined with C021 in targeting ROR1+ NB. We found that C021-infected NB cells secreted hIL-21 in vitro and in vivo. Compared to the non-cytokine-secreting parental virus C134, C021 significantly enhanced the in vitro cytotoxicity (p < 0.05) of anti-ROR1-CAR-NK cells with increased interferon (IFN)-γ (p < 0.05), granzyme B (p < 0.05), and perforin (p < 0.05) secretion against NB cells. Furthermore, the combination of C021 and anti-ROR1-CAR-NK cells significantly extended the survival of human NB xenografted NSG mice compared to controls (mock NK, ROR1-CAR-NK, C134, C021, C134+ROR1-CAR-NK, and C021+mock NK). Our results suggest that cytokine-secreting oncolytic virus in combination with CAR-NK cells is a novel, effective immunotherapeutic approach for high-risk NB.

Chimeric antigen receptor (CAR) immunotherapy has revolutionized anticancer therapy, as it accurately targets cancer cells by recognizing specific antigens expressed in cancer cells. This innovative therapeutic strategy has attracted considerable attention. However, few therapeutics are available for treating non-small cell lung cancer (NSCLC), which accounts for most lung cancer cases and is one of the deadliest cancers with low survival rates.

In this study, we developed a new antibody targeting erythropoietin-producing hepatocellular carcinoma A2 (EphA2), which is highly expressed in NSCLC, and established CAR-T/ natural killer (NK) immune cells to verify its potential for immune cell therapy. The killing capacity, cytokine secretion and solid tumor growth inhibition of EphA2 CAR-T/NK cells were compared to normal T/NK cells.

EphA2 CAR-T cells demonstrated superior killing capacity, enhanced cytokine secretion, and significant solid tumor growth inhibition. Additionally, they exhibited improved tumor infiltration in lung cancer models compared to normal T cells. The anticancer efficacy of the developed EphA2 CAR-NK cells was also confirmed, showcasing their potential as robust candidates for immune cell therapy.

The findings of this study highlight the potential of CAR-T/NK cell therapy targeting EphA2 as an effective treatment for lung cancer, particularly NSCLC with high EphA2 expression. By leveraging the specific targeting capabilities of CAR-T cells and the unique properties of CAR-NK cells, this approach provides a promising therapeutic strategy to address the unmet needs in NSCLC treatment.

Tyrosine kinase 2 (TYK2) deficiency and loss or inhibition of kinase activity in men and mice leads to similar immune compromised phenotypes, predominantly through impairment of interferon (IFN) and interleukin 12 family responses. Here we relate the transcriptome changes to phenotypical changes observed in TYK2-deficient (Tyk2-/-) and TYK2 kinase-inactive (Tyk2K923E) mice in naïve splenic immune cells and upon ex vivo IFN treatment or in vivo tumor transplant infiltration. The TYK2 activities under homeostatic and both challenged conditions are highly cell-type-specific with respect to quantity and quality of transcriptionally dependent genes. The major impact of loss of TYK2 protein or kinase activity in splenic homeostatic macrophages, NK and CD8+ T cells and tumor-derived cytolytic cells is on IFN responses. While reportedly TYK2 deficiency leads to partial impairment of IFN-I responses, we identified cell-type-specific IFN-I-repressed gene sets completely dependent on TYK2 kinase activity. Reported kinase-inactive functions of TYK2 relate to signaling crosstalk, metabolic functions and cell differentiation or maturation. None of these phenotypes relates to respective enriched gene sets in the TYK2 kinase-inactive cell types. Nonetheless, the scaffolding functions of TYK2 are capable to change transcriptional activities at single gene levels and chromatin accessibility at promoter-distal regions upon cytokine treatment most prominently in CD8+ T cells. The cell-type-specific transcriptomic and epigenetic effects of TYK2 shed new light on the biology of this JAK family member and are relevant for current and future treatment of autoimmune and inflammatory diseases with TYK2 inhibitors.

Despite decades of insights about the role of natural killer (NK) cells in HIV infection, their persistent dysregulation despite antiretroviral therapy (ART) and its pathological consequences have been incompletely delineated. In this review, we highlight recent findings on the immunophenotypic and functional alterations of NK cells during virally suppressed HIV infection and explore their potential impact on promoting non-AIDS related comorbidities among people living with HIV (PLWH).

Of note are the apparent persistent activated profiles of NK cells and pathophysiological events such as endoplasmic reticulum (ER) stress in potentially driving NK cell derived inflammation and tissue destruction. Additionally, recent interest in trained immunity is discussed as a potential mediator of ongoing NK cell dysregulation, contributing to comorbidities such as cardiovascular disease and neurocognitive disorders, both with an inflammatory etiology.

Clinical and mechanistic evidence suggests persistent activation and dysregulation of the innate immune system are major drivers of non-AIDS comorbidities during virally suppressed HIV infection. Delineating the mechanistic role of specific components of innate immunity such as NK cells in inducing these pathologies will lead to the identification of novel therapeutic/prophylactic strategies to improve the overall health of PLWH.

The genome-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the past nearly 5 years since its emergence has refreshed our understanding of virus evolution, especially on convergent co-evolution with the host. SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations that affect the functional properties of the virus by altering its infectivity, virulence, transmissibility, and interactions with host immunity. This poses a huge challenge to global prevention and control measures based on drug treatment and vaccine application. As one of the key evasion strategies in response to the immune profile of the human population, there are overwhelming amounts of evidence for the reduced antibody neutralization of SARS-CoV-2 variants. Additionally, data also suggest that the levels of CD4+ and CD8+ T-cell responses against variants or sub-variants decrease in the populations, although non-negligible cross-T-cell responses are maintained. Herein, from the perspectives of structural immunology, we outline the characteristics and mechanisms of the T cell and antibody responses to SARS-CoV and its variants/sub-variants. The molecular bases for the impact of the immune escaping variants on the interaction of the epitopes with the key receptors in adaptive immunity, that is, major histocompatibility complex (MHC), T-cell receptor (TCR), and antibody are summarized and discussed, the knowledge of which will widen our understanding of this pandemic-threatening virus and assist the preparedness for Pathogen X in the future.

Post-transplant cyclophosphamide (PTCy) has contributed to the success of haploidentical hematopoietic stem cell transplantation (HSCT) and is also used in transplantation from matched donors. However, limited data on the immune reconstitution after this type of immunosuppression is available. We aimed to evaluate immune reconstitution after HSCT from unrelated donors, comparing anti-thymocyte globulin (ATG) and PTCy. Consecutive patients undergoing HSCT from unrelated donors and receiving either ATG or PTCy were prospectively included. Immune reconstitution analyses were performed by flow cytometry pre-transplant and on days 30, 60, 90, and 180 post-transplant. We included 36 patients, 20 in the ATG group and 16 in the PTCy group. In the early post-transplant period (day [d]+30), the ATG group showed a higher number of total lymphocytes, T, B, and natural killer (NK) cells compared to the PTCy group. However, at d+180, the PTCy group exhibited a higher number of B cells. On d+60 and d+90, the ATG group displayed higher number of NK cells CD56dim compared to the PTCy group, while on d+180, the PTCy group showed higher number of CD56-, CD16+, and, NKG2D+ NK cells. Naive CD4+, transition CD4+, and naive CD8+ T cells on d+60 were identified as risk factors for acute graft-versus-host disease grade 2-4, and a higher count of CD4+ memory cells on d+180 was identified as a risk factor for chronic graft-versus-host disease. In the context of unrelated allogeneic transplantation, immunosuppression with PTCy was associated with later B-, T- and NK-cell reconstitution compared to ATG.

Ischemic stroke is a devastating neurological disease. Brain ischemia impairs systemic immune responses and heightens susceptibility to infections, though the underlying mechanisms remain incompletely understood. Natural killer (NK) cells exhibited decreased frequency and compromised function after acute stage of stroke, resulting in NK cell-associated immune deficiency and increased risk of infection. MicroRNAs (miRNAs) are post-transcriptional molecular modulators. Our previous study revealed a significant upregulation of miR-451a in circulating NK cells from patients with ischemic stroke, but its effects and precise mechanism on immune defense remain elusive. In this study, we observed a substantial elevation of miR-451a level in brain and splenic NK cells in murine model of ischemic stroke miR-451a mimics suppressed NK cell activation and cytotoxicity within the ischemic brain and periphery, including a downregulation of activation marker CD69, and reduced production of effector molecules IFN-γ and perforin. Conversely, miR-451a inhibitor preserved NK cell activation and cytotoxicity, rescuing local inflammation, and reducing bacterial burden in the lung. Pharmacological inhibition of Akt-mTOR pathway with AZD8055 effectively blocked the impacts of miR-451a on NK cell functions. Collectively, these findings suggest miR-451a negatively regulates NK cell cytotoxicity in both the brain and periphery, which could be re-addressed by modulating the Akt-mTOR signaling pathway.

Natural killer (NK) cells, which exert spontaneous cytotoxicity against infectious diseases and cancer, also play an important role in leukemia therapy. Despite the success of NK-based therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in these hematologic malignancies remains elusive. The aim of the present study was to investigate whether allogeneic NK cells combined with aclacinomycin (ACM) could enhance anti-leukemic functionality against an acute myeloid leukemia (AML) cell line and to clarify the underlying mechanism.

KG-1α and HL-60 AML cell lines were subjected to different treatments. The effects of different drug combinations on cytotoxicity, cell viability, and apoptotic status were examined.

The results showed that the combination of ACM (40 nmol/l) and allogeneic NK cells (ratio 20:1) was significantly cytotoxic to AML cells and increased the apoptosis of AML cells, especially after 72 h of treatment. Subsequent analyses revealed that the expression of immunogenic cell death (ICD)-related molecules calreticulin, adenosine triphosphate, and high mobility group box 1, as well as NK cell effector production-perforin and granzyme B-was markedly increased in the combination treatment group. These findings suggest that ACM enhances the anti-leukemic activity of allogeneic NK cells through the ICD pathway.

These results demonstrated that allogeneic NK cells had enhanced functional responses when stimulated with ACM in vitro, exhibiting superior effector cytokine production and cytotoxicity compared to the control, which contained conventional NK cells. In conclusion, the present study suggested that the combination of ACM and allogeneic NK cells is a promising therapeutic strategy against AML.

Renal cell carcinoma (RCC) is a malignancy that makes up 3% of adult cancers and 20%-30% of patients were diagnosed with metastatic RCC in the beginning, while the median overall survival (OS) of metastatic RCC systemic therapy ranges from 16 months to 50 months. Immunotherapy, a novel therapy that relies on the specific binding of immune cells and tumor cells, may be a potential therapy for advanced renal cell carcinoma. While chimeric antigen receptor NK-cell (CAR-NK) therapy has been investigated in a variety of solid tumors, specific research on its application to RCC has also been reported by several teams. In this review, we introduced the cytotoxicity mechanisms of NK cells, summarized the connections between RCC and NK cells, and posted new insights into renal cell carcinoma CAR-NK therapy. To date, most researches focusing on renal cell carcinoma and NK cells only claimed the mechanisms of NK cell cytotoxicity and NK cell immune suppression and even immune escape, yet the molecules involved could also be interesting targets for renal cell carcinoma CAR-NK therapy.

Natural Killer (NK) cells are innate immune cells that can directly detect and kill cancer cells. Understanding the molecular determinants regulating human NK cell cytotoxicity could help harness these cells for cancer therapies. To this end, we compared the transcriptome of NK cell clones derived from human peripheral blood, which were strongly or weakly cytotoxic against 721.221 and other target cells. After one month of culture, potent NK cell clones showed a significant upregulation in genes involved in cell cycle progression, suggesting that proliferating NK cells were particularly cytotoxic. Beyond two months of culture, NK cell clones which were strongly cytotoxic varied in their expression of 28 genes, including CD8Α and CD70; NK cells with high levels of CD70 expression were weakly cytotoxic while high CD8Α correlated with strong cytotoxicity. Thus, NK cells were cultured and sorted for expression of CD70 and CD8α, and in accordance with the transcriptomic data, CD70+ NK cells showed low cytotoxicity against 721.221 and K562 target cells. Cytotoxicity of CD70+ NK cells could be enhanced using blocking antibodies against CD70, indicating a direct role for CD70 in mediating low cytotoxicity. Furthermore, time-lapse microscopy of NK cell-target cell interactions revealed that CD8α+ NK cells have an increased propensity to sequentially engage and kill multiple target cells. Thus, these two markers relate to NK cell populations which are capable of potent killing (CD70-) or serial killing (CD8α+).

As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.

This study aimed to assess the evolution, trends, and research hotspots of publications related to natural killer (NK) cells and miscarriage.

The literature on NK cells and miscarriage was retrieved from the Web of Science Core Collection. VOSviewer and CiteSpace were used to analyze the publication years, countries, institutions, journals, highly cited authors, categories, and citation bursts of keywords.

A total of 1,275 articles were analyzed. The annual publication outputs showed steady growth, with the majority of publications in 2020 and citations in 2022. The number of publications in this field fluctuated from 1981 to 2023, with a slight downward trend observed. However, the number of citations increased steadily until 2023, followed by a minor decline. The United States contributed the highest number of publications and had the highest h-index. The American Journal of Reproductive Immunology ranked first in terms of number of publications and h-index. Reproductive biology, immunology, and obstetrics and gynecology were the most representative disciplines. Kwak-kim J, Chaouat G, and Croy BA were the top three most productive authors in the field. Keyword burst analysis demonstrated that the immune system and cytotoxicity receptors were current research hotspots.

This is the first bibliometric study to comprehensively summarize trends and advances in the study of NK cells in miscarriage. This information highlights the recent research frontiers and emerging directions and provides a reference for subsequent research in the future.

The role of natural killer (NK) cells in the management of prostate cancer (PCa) remains incompletely understood. Some have proposed that measuring NK cells in blood samples could serve as a reliable, minimally invasive tool for screening, assessing treatment effects, and predicting survival outcomes in PCa patients. However, the significance of different NK cell phenotypes remains unclear. Given the interplay between NK cells and the microbiome, we hypothesize that a combined signature of NK cell phenotypes derived from blood, along with microbiome profiles from oral, urine, and stool samples, could serve as a surrogate marker for NK cell activity in tumor and its microenvironment. Such an approach provides a practical alternative to invasive tumor biopsies by enabling the indirect assessment of NK cell function in tumors. Additionally, profiling NK cell phenotypes and their interactions with the microbiota has the potential to enhance prognostic accuracy and guide the development of personalized therapeutic strategies. Prospective studies are needed to validate the utility of NK cell and microbiome assays in personalized PCa management, with a focus on minimally invasive procedures and predictive signatures for treatment outcomes.

The emergence of the COVID-19 pandemic made it critical to understand the immune and inflammatory responses to the SARS-CoV-2 virus. It became increasingly recognized that the immune response was a key mediator of illness severity and that its mechanisms needed to be better understood. Early infection of both tissue and immune cells, such as macrophages, leading to pyroptosis-mediated inflammasome production in an organ system critical for systemic oxygenation likely plays a central role in the morbidity wrought by SARS-CoV-2. Delayed transcription of Type I and Type III interferons by SARS-CoV-2 may lead to early disinhibition of viral replication. Cytokines such as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor α (TNFα), some of which may be produced through mechanisms involving nuclear factor kappa B (NF-κB), likely contribute to the hyperinflammatory state in patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) cells, CD8+ T-cells, and B-cells, can contribute to disease severity and may reflect direct cytopathic effects of SARS-CoV-2 or end-organ sequestration. Direct infection and immune activation of endothelial cells by SARS-CoV-2 may be a critical mechanism through which end-organ systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation and microthrombi development can be seen in the lungs and other critical organs throughout the body, such as the heart, gut, and brain. The kidney may be among the most impacted extrapulmonary organ by SARS-CoV-2 infection owing to a high concentration of ACE2 and exposure to systemic SARS-CoV-2. In the kidney, acute tubular injury, early myofibroblast activation, and collapsing glomerulopathy in select populations likely account for COVID-19-related AKI and CKD development. The development of COVID-19-associated nephropathy (COVAN), in particular, may be mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling, suggesting a direct connection between the COVID-19-related immune response and the development of chronic disease. Chronic manifestations of COVID-19 also include systemic conditions like Multisystem Inflammatory Syndrome in Children (MIS-C) and Adults (MIS-A) and post-acute sequelae of COVID-19 (PASC), which may reflect a spectrum of clinical presentations of persistent immune dysregulation. The lessons learned and those undergoing continued study likely have broad implications for understanding viral infections' immunologic and inflammatory consequences beyond coronaviruses.

Immune checkpoint blockade (ICB) therapy, including antibodies targeting the programmed cell death protein 1 (PD-1) pathway, has significantly prolonged the overall survival (OS) in patients with advanced cervical cancer (CC). ICB treatment affects both target cells and various components released by immune cells, which can be observed in peripheral blood. However, there has been limited research on the dynamics of peripheral blood immunophenotyping and its association with OS in CC patients receiving ICB therapy.

Patients with persistent, recurrent, or metastatic CC treated with ICB were enrolled between December 2019 and September 2022. The dynamic changes in peripheral blood immune cells, immunoglobulins, and complement components were analyzed at baseline (within 30 days prior to the first ICB cycle) and after the second cycle of ICB treatment (4-6 weeks after the first ICB treatment). Associations of the baseline levels of peripheral blood immune cells, immunoglobulins, complement components with OS were analyzed using multivariable Cox regression analysis.

In this retrospective cohort study, 119 patients who received at least two cycles of ICB were included. Data on peripheral blood immune cells, immunoglobulins, and complement components were available for 70 of these patients. The percentages of suppressor T (Ts) cells and natural killer (NK) cells in peripheral blood increased significantly post-ICB treatment, whereas the Th/Ts ratio and IgM levels decreased. The percentages of cytotoxic T (Tc) cells, Ts cells, the Th/Ts ratio, and levels of IgM, IgA, C3, and C4 were significantly associated with the OS of patients. Furthermore, multivariable Cox regression analysis found that a high level of IgA was associated with poor OS of the patients (HR = 2.918; 95% CI, 1.081-7.877, P = 0.035).

Our study demonstrated the potential proliferation of peripheral blood anti-tumor T cells in some CC patients undergoing ICB therapy. The observed associations between peripheral blood immunophenotyping and OS suggest that these biomarkers might have potential as prognostic tools.

Immune cell engagers (ICEs) are an emerging class of immunotherapies designed to harness the immune system's anti-tumor potential through precise targeting and activation of immune effector cells. By engaging T cells, natural killer (NK) cells, and phagocytes, ICEs overcome challenges such as immune evasion and MHC downregulation, addressing critical barriers in cancer treatment. T-cell engagers (TCEs), led by bispecific T-cell engagers (BiTEs), dominate the field, with innovations such as half-life-extended BiTEs, trispecific antibodies, and checkpoint inhibitory T-cell engagers driving their application in hematologic and solid malignancies. NK cell engagers (NKCEs) and phagocyte cell engagers (PCEs) are rapidly progressing, drawing on NK cells' innate cytotoxicity and macrophages' phagocytic abilities to target tumors, particularly in immunosuppressive microenvironments. Since the FDA approval of Blinatumomab in 2014, ICEs have transformed the oncology landscape, with nine FDA-approved products and numerous candidates in clinical trials. Despite challenges such as toxicity, resistance, and limited efficacy in solid tumors, ongoing research into advanced platforms and combination therapies highlights the growing potential of ICEs to provide personalized, scalable, and effective cancer treatments. This review investigates the mechanisms, platforms, research trends, and clinical progress of ICEs, emphasizing their pivotal role in advancing precision immunotherapy and their promise as a cornerstone of next-generation cancer therapies.

Diabetic cardiomyopathy (DCM) is one of the cardiovascular complications of diabetes, characterized by the development of ventricular systolic and diastolic dysfunction due to factors such as inflammation, oxidative stress, fibrosis, and disordered glucose metabolism. As a sustainable therapeutic approach, exercise has been reported in numerous studies to regulate blood glucose and improve abnormal energy metabolism through various mechanisms, thereby ameliorating left ventricular diastolic dysfunction and mitigating DCM. This review summarizes the positive impacts of exercise on DCM and explores its underlying molecular mechanisms, providing new insights and paving the way for the development of tailored exercise programs for the prophylaxis and therapy of DCM.

Natural killer (NK) cell development and functionality rely on precise regulation by specific transcription factors (TFs). Our study demonstrates that the nuclear orphan receptor NR2F6 represses the expression of the activating receptor NKp46, an established key player in NK cell-mediated cytotoxicity during infection and tumor rejection. Despite normal NK cell development in the bone marrow, germline Nr2f6-deficient mice exhibit impaired terminal maturation of NK cells in the periphery. Short-term NK cell responses to lipopolysaccharide (LPS) activation, independent of NKp46, are subsequently reduced in Nr2f6-deficient mice. Conventional type 1 dendritic cells (cDC1) and macrophage populations are decreased in spleens of Nr2f6-deficient mice, subsequently, IL-15-dependent NK cell priming is limited. Administration of exogenous IL-15 in vitro and as IL-15 complex in vivo can compensate for these deficits, promoting terminal maturation of NK cells in Nr2f6-deficient mice. Subsequent transcriptome analysis reveals significant changes in gene expression profiles of NK cells from IL-15 complex treated Nr2f6-deficient mice, with notable alterations in essential NK genes such as Klrg1, Prdm1, Stat5a, Zeb2, and Prf1. Consequently, Nr2f6-deficient IL-15 complex-treated NK cells raise enhanced effector responses of IFNγ, Perforin, and Granzyme B upon ex vivo activation. Of importance, Nr2f6-deficient mice are protected against MHC-I negative B16-F10 melanoma lung metastasis formation, especially with IL-15 complex treatment, indicating the potential of NR2F6 to affect NKp46-dependent NK cell-mediated tumor surveillance. The therapeutic targeting of NR2F6 may be a promising strategy for boosting NKp46-dependent NK-cell-mediated tumor surveillance and metastasis.

In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.