Obesity is associated with increased risk of cancer, including endometrial, esophageal, gastric, kidney, colorectal, liver, gallbladder, pancreas, prostate, postmenopausal breast, ovarian, and thyroid cancers. Overweight and obesity account for approximately 10% of new cancer diagnoses annually in the US and up to 50% of certain cancers such as endometrial and hepatobiliary cancer. Overweight is defined as body mass index (BMI) of 25 to 29.9 and obesity as BMI of 30 or greater. Obesity and overweight are characterized by excess accumulation of adipose tissue, which disrupts its primary function of energy storage. Excess energy, in the form of free fatty acids, is transferred to developing cancer cells and stimulates cancer development through genomic instability caused by oxidative stress and DNA damage. Other defining features of adipose tissue dysfunction include inflammation and altered hormone production such as increased estrogens and leptin and decreased adiponectin. Inflamed adipose tissue is associated with systemic elevations in inflammatory mediators, such as prostaglandin E2, the cytokines interleukin 1β and interleukin 6, and tumor necrosis factor α. These mediators promote tumor growth directly or indirectly by stimulating estrogen biosynthesis, which can promote proliferation of hormone-sensitive cancers such as breast, ovarian, and endometrial cancer, or by suppressing immune-mediated elimination of developing cancer cells through accumulation of myeloid-derived suppressor cells and reductions in the amount and function of cytotoxic T cells and natural killer cells. Inflammation and oxidative stress are also stimulated by obesity-associated depletion of gut commensal bacteria species (eg, Akkermansia muciniphila) and overgrowth of bacterial populations associated with cancer development in preclinical models (eg, Bilophila). In observational studies, patients who lost more than 10% of body weight through bariatric procedures (n = 30 318) or with glucagon-like peptide 1 receptor agonists (n = 1 651 452) had modest reductions in obesity-associated cancer incidence (absolute change, -0.02% to -0.5%). Overweight and obesity are associated with higher rates of cancer and account for 10% of new cancer diagnoses annually in the US. Weight loss may reduce cancer risk by attenuating adverse effects of obesity, but greater than 10% weight loss may be necessary to reduce cancer risk.

Angiotensin-converting enzyme 2 (ACE2) has been implicated as an oncogene in certain cancer types; however, there is a lack of analysis on the role of ACE2 in the predictive value for prognosis and immunotherapy response in various tumor types. This study used data from the Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER 2.0), cBioPortal, and ROC Plotter databases to analyze the expression, prognosis, and immune cell infiltration of ACE2 in various tumor types. Furthermore, we analyzed the correlation between the expression of ACE2 and clinicopathological characteristics in 119 pairs of colorectal cancer (CRC) tissues using immunohistochemistry analysis, and then conducted the in vitro experiments to verify the role of ACE2 in the migration and proliferation of CRC cells. We found that ACE2 was highly expressed in CRC tissues compared with adjacent normal tissues, and that CRC patients with high ACE2 expression levels showed poor survival. Additionally, combined bioinformatics and qRT-PCR analysis identified a strong negative correlation between ACE2 expression and natural killer cell infiltration in CRC. Meanwhile, ACE2 expression was significantly elevated in patients resistant to anti-CTLA-4 and anti-PD-L1 therapy and was linked to poor prognosis. In vitro experiments showed that silencing ACE2 inhibits the proliferation and invasion of CRC cells. These results highlight ACE2's involvement in CRC pathogenesis and cancer-immune interactions, positioning it as a promising prognostic and therapeutic biomarker in CRC.

Natural killer cells as biomarkers for disease activity, lupus nephritis, and time to remission in treatment-naïve childhood-onset systemic lupus erythematosus: a cohort study.

Background: Latent tuberculosis infection (LTBI) is the principal reservoir for active tuberculosis, with >85% of cases attributable to reactivation. Bacillus Calmette-Guérin fails to block this transition, leaving a critical gap in prevention. Methods: An immunoinformatics/reverse-vaccinology pipeline was applied to seven dormancy-related antigens retrieved from Mycobrowser. T-cell epitopes were predicted with NetMHCI/IIpan-4.1 and B-cell epitopes with ABCpred; antigenicity, allergenicity, and toxicity were evaluated with VaxiJen, AllerTOP, and ToxinPred. Secondary/tertiary structures were modeled with PSIPRED and AlphaFold-3; docking to Toll-like receptors (TLR) 2/4 and 100 ns molecular dynamics simulations assessed complex stability. Immune responses were simulated with C-ImmSim, and the mRNA sequence was human-codon-optimized using ExpOptimizer. Results: The resulting construct, RP14914P, encodes 14 cytotoxic T lymphocyte, 9 helper T lymphocyte, and 14 B-cell epitopes within an 866-aa, 90.4 kDa polypeptide. Antigenicity score = 0.7797, immunogenicity score = 8.58629. and no toxicity or allergenicity was predicted. Physicochemical analysis: instability index = 28.65, and solubility = 0.513. Estimated population coverage is 82.35% and 99.67% for Human Leukocyte Antigen (HLA)-I and HLA-II globally. Docking energies: −1477.8 kcal/mol (TLR2) and −1480.1 kcal/mol (TLR4). Molecular dynamics trajectories confirm stable binding. Immune simulation predicts potent activation of Natural Killer cells, macrophages, and dendritic cells, Th1 polarization, high interferon-γ/interleukin-2 secretion, and durable memory. Conclusions: In silico analyses predict that RP14914P exhibits favorable immunogenicity, safety, and broad population coverage, suggesting its potential as a promising mRNA vaccine candidate to prevent LTBI reactivation. However, these computational predictions require thorough experimental validation to confirm the vaccine’s immunogenicity and protective efficacy.

In the innate immune system, natural killer (NK) cells are effector lymphocytes which control several tumor types and microbial infections by limiting disease spread and tissue damage. With tumor cell killing abilities, with no priming or prior activation, NKs are potential anti-cancer therapies. In clinical practice, NKs are used in intravenous injections as they typically grow as suspension, similar to other blood cells. In this study, we designed a novel and effective biomaterial-based platform for NK cell delivery, which included in situ NK cell encapsulation into three-dimensional (3D) biocompatible polymeric scaffolds for potential anti-cancer treatments. Depending on physical cross-linking between an alginate (ALG) polymer and a divalent cation, two natural polymers (gelatin (GEL) and hyaluronic acid (HA)) penetrated into pores and generated an inter-penetrating hydrogel system with improved mechanical properties and stability. After extensive characterization of hydrogels, NK cells were encapsulated inside using our in situ gelation procedure to provide a biomimetic microenvironment.

HIF-1α+ CD4+ T cells coordinate a tissue-resident immune cell network in the lung.

Off-the-shelf CAR natural killer progenitor cell therapies are built to last.

The p53 tumor suppressor modulates the expression of proteins that control natural killer cell activity

Non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), exhibits marked tumor heterogeneity and poor prognosis. Metabolic reprogramming is a hallmark of cancer, and long non-coding RNAs (lncRNAs) have emerged as important regulators of tumor metabolism and immune interactions. This study aimed to systematically characterize metabolism-related lncRNAs in NSCLC using single-cell and bulk transcriptomic data, and to evaluate their associations with tumor heterogeneity, immune microenvironment, and clinical outcomes. RNA sequencing and clinical data for LUAD and LUSC were obtained from The Cancer Genome Atlas. Metabolism-related lncRNAs were identified through partial correlation analysis combined with KEGG pathway-based gene set enrichment analysis. Tumor microenvironment characteristics were assessed using CIBERSORTx. Consensus clustering based on the top 20 metabolism-related lncRNAs was applied to define molecular subtypes. Cis- and trans-regulatory relationships were explored using Spearman correlation, and competing endogenous RNA networks were constructed by integrating TargetScan-predicted miRNA-mRNA interactions. Findings were validated across six independent datasets, and single-cell transcriptomic data were used to assess cell-type-specific expression patterns. A subset of metabolism-related lncRNAs was significantly enriched among differentially expressed and survival-associated lncRNAs in NSCLC. AL365181.2 was identified as a key lncRNA associated with multiple metabolic pathways and poor prognosis. Single-cell analysis revealed immune cell-specific expression patterns, particularly in B cells, CD8+ T cells, and natural killer cells. Metabolic lncRNA-based clustering defined distinct molecular subtypes with significant differences in immune profiles and clinical outcomes. Metabolism-related lncRNAs contribute substantially to tumor heterogeneity and prognosis in NSCLC and may serve as valuable biomarkers for patient stratification and personalized therapeutic strategies.

Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.

Siglecs, a family of sialic acid (Sia)-binding immunomodulatory receptors selectively expressed on immune cells, are promising immunotherapeutic targets. While synthetic Sia derivatives can manipulate the Sia-Siglec axis with high affinity, their therapeutic application has been hampered by the poor substrate tolerance of wild-type CMP-sialic acid synthase (CSS) for sterically demanding analogs. Here, we report a structure-guided engineering strategy to evolve Neisseria meningitidis CMP-Sia synthetase (NmCSS) for enhanced activity with bulky substrates. Coupling this optimized NmCSS variant with a sialyltransferase enabled a scalable "one-pot two-enzyme" (OPTE) synthesis of diverse sialoside analogs. Screening this library on glycan microarrays revealed novel high-affinity ligands with selective Siglec binding profiles. Leveraging the OPTE system, we achieved single-step glycoengineering of natural killer (NK)-92MI cells with tailored Siglec-2 or Siglec-3 ligands, which exhibited potent cytotoxicity against B-cell lymphoma (Siglec-2+) and acute myeloid leukemia (Siglec-3+) models. These engineered NK cells displayed significantly enhanced tumor killing capacity, mediated by enhanced granzyme release and cytokine production while maintaining excellent cell viability. This modular platform addresses critical limitations in enzymatic synthesis of modified sialosides and their efficient display on therapeutic cells. Our work establishes a versatile and practical platform for developing next-generation immunotherapies that precisely target the Sia-Siglec axis with improved specificity and functionality.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis, and patient mortality due to the absence of effective therapies. Hypoxia-inducible factor 1 (HIF-1) regulates the expression of thousands of RNAs in TNBC. Here, we demonstrate that transcription of the ISG20 gene, which encodes an RNA exonuclease, is activated by HIF-1 in TNBC cells. ISG20-mediated degradation of RHOBTB3 mRNA increases HIF-1α protein expression and activates NANOG signaling, which increases breast cancer stem cell specification and lung metastasis. ISG20 also degrades STAT1 and IRF1 mRNAs, leading to decreased expression of CXCL10 and impaired recruitment of CD8+ T cells and natural killer cells, thereby promoting breast cancer immune evasion. Silencing ISG20 increases the sensitivity of mouse TNBC cells to anti-PD1 antibody immune checkpoint blockade. Our data suggest that targeting ISG20, in combination with immunotherapy, could be an effective therapeutic strategy for TNBC.

Successful pregnancy requires precise immune interactions between fetal extravillous trophoblasts (EVT) and maternal decidual immune cells at the maternal-fetal interface. Glycosylation, particularly terminal sialylation, is emerging as a key modulator of these interactions; however, its functional role in regulating the EVT-immune crosstalk remains poorly defined. Here, we aimed to identify a critical sialic acid-Siglec-7-IL-8-STAT3 signaling axis that promotes EVT invasiveness and is disrupted during recurrent pregnancy loss (RPL). Using primary human tissues and organ-on-chip models, we demonstrate that EVTs from patients with RPL exhibit reduced sialylation, coinciding with an increased proportion of Siglec-7⁺ decidual natural killer (dNK) cells. Mechanistically, sialylated glycoproteins on EVT surfaces engage Siglec-7, stimulating IL-8 secretion by dNK cells, which, in turn, activates STAT3 in EVTs to enhance migration and invasion. Restoration of EVT sialylation re-engages Siglec-7, rescues IL-8-STAT3 signaling, and restores invasive capacity. Our findings reveal that defective EVT sialylation disrupts a key immunological checkpoint that normally promotes EVT invasion and potentially contributes to RPL. This work provides direct mechanistic evidence that specific glycan-encoded immune signals at the maternal-fetal interface are critical for healthy pregnancy outcomes and suggests that modulating sialylation may offer a therapeutic strategy for RPL.Proposed model of sialic acid-Siglec-7-mediated regulation of EVT invasion through the ST6GALNAC6-sialic acid-Siglec-7-IL-8-STAT3 signaling axis. Schematic representation of the working model: enhanced sialylation of EVT membrane glycoproteins-driven by ST6GALNAC6-facilitates recognition by Siglec-7 expressed on dNK cells. This interaction promotes the activation of the IL-8-STAT3 signaling pathway, which supports EVT cell migration and invasion. Disruption of sialylation or Siglec-7 engagement impairs this pathway and reduces EVT invasiveness, potentially contributing to the pathogenesis of RPL. Figure created with BioRender.com (https://BioRender.com/dxxt5az).

Natural killer cells, macrophages and dendritic cells as innate immune therapies for blood cancers.

Natural killer (NK) cells are critical regulators of immune balance at the maternal-fetal interface. T-bet (Tbx21) is a key transcription factor shaping NK cell effector functions, yet its role in decidual NK (dNK) cell adaptation across gestation remains unclear. We used a T-bet fate-mapping mouse model (Rosa26RFP × Tbx21Cre) to track developmental and functional reprogramming of NK cells in the uterus, decidua, and placenta throughout pregnancy. Analyses included flow cytometry, bulk RNA sequencing of fate-mapped cells, and single-cell transcriptomic profiling of CD45+Lineage- immune populations at mid and late gestation. We found that NK cells with a history of T-bet expression (RFP+) progressively downregulate T-bet in a tissue and gestation-specific manner, particularly within decidual and placental compartments. Despite this loss, RFP+ cells retained core NK cell markers and altered their lineage identity towards ILC2 or ILC3 fate. Bulk transcriptomic analysis revealed that T-bet downregulation is associated with dampened IFN-γ, and cytotoxic pathways and increased expression of tissue-residency associated transcriptional regulators. Single-cell RNAseq revealed a gestational transition in dNK subset composition, with a decline in cytotoxic tissue-resident NK cells and expansion of regulatory and conventional NK subsets by late gestation. These findings identify a novel transcriptional program that shapes NK cell plasticity in response to T-bet downregulation across gestation. Rather than undergoing lineage diversion, dNK cells adapt to the decidual environment via transcriptional compensation and subset redistribution during pregnancy. This work sheds light on the temporal coordination of innate immune function relevant to pregnancy success.

Breast cancer progression is increasingly recognized as an immunometabolic disorder in which tumor-intrinsic metabolic reprogramming and microenvironmental stress converge to impair innate immune surveillance. Beyond its established role in glycemic control, metformin has emerged as a promising immunometabolic modulator with anticancer potential. Accumulating evidence indicates that metformin suppresses breast tumor growth by targeting key metabolic vulnerabilities, including dysregulated glycolysis, lipid metabolism, and mitochondrial energetics, while simultaneously restoring the functional competence of innate immune effectors, particularly natural killer (NK) and natural killer T (NKT) cells. At the molecular level, metformin engages AMP-activated protein kinase (AMPK)-centered signaling and mitochondrial complex I-associated energetic stress, leading to downstream modulation of mTOR activity, redox balance, autophagy, and RNA-mediated regulatory networks. These coordinated effects reduce tumor cell plasticity and enhance immune permissiveness. Within the tumor microenvironment, metformin attenuates hormone-dependent stromal support, disrupts immunosuppressive myeloid networks, normalizes chemokine and cytokine profiles, and promotes antigen presentation and innate immune cell recruitment. Preclinical studies consistently demonstrate delayed tumor onset, suppression of aggressive breast cancer subtypes, impairment of cancer stem cell maintenance, and reinforcement of NK/NKT-mediated antitumor surveillance following metformin treatment. However, emerging clinical and translational evidence suggests that therapeutic efficacy is context dependent, influenced by tumor molecular subtype, host metabolic status, immune composition, and pathway-specific biomarker engagement. This review critically synthesizes mechanistic, preclinical, and clinical findings to position metformin as a host-directed immunometabolic adjuvant in breast cancer. Integrating insights from metabolism, innate immunology, pharmacology, and biotechnology, this work highlights opportunities for biomarker-guided stratification and rational combination strategies aimed at enhancing NK/NKT-cell-driven antitumor immunity in breast cancer therapy.

Immunosenescence represents a critical aspect of the aging process. Centenarians, serving as a nature model of "healthy aging," demonstrate a distinctive immune "compensatory adaptation" mechanism that contributes to the maintenance of immune homeostasis. However, the specific immune cell subsets involved and the molecular mechanisms underlying these phenotypic traits remain incompletely understood. In this study, we integrated single-cell RNA sequencing data spanning the entire lifespan of East Asian populations with bulk transcriptomic data from a centenarian cohort in Guangxi. Utilizing the Scissor algorithm, we identified immune cell subpopulations positively (Scissor+) and negatively (Scissor-) associated with longevity phenotypes, thereby constructing an immune cell atlas of "Longevity Molecular Tag." Our findings indicate that Scissor+ cells predominantly comprise natural killer (NK) cells, CD8+ T cells, and γδ T cells, characterized by enhanced cytotoxic and immunomodulatory functions. Conversely, Scissor- cells mainly include CD4+ T cells, B cells, and dendritic cells (DCs), which are linked to inflammatory signaling pathways and Th17/Th1 differentiation. Trajectory analysis elucidated the differentiation pathways of NK, CD8+ T cells, CD4+ T cells, and B cells. Differentially expressed genes were enriched in pathways such as NF-κB signaling, T cell receptor signaling, and NK cell cytotoxicity. Furthermore, co-localization analysis revealed five eQTL-colocalized events (rs3793537-GLIPR2/CD72/TLN1 and rs8019902-TRDV2/TRDC) associated with longevity. Collectively, these results suggest that centenarians achieve immune equilibrium by remodeling cytotoxic immune lineages and finely tuning inflammatory responses, thereby promoting health span and longevity. This study offers novel insights into potential strategies for modulating immunosenescence.

Expanded adaptive NKG2C+ NK cells exhibit potent ADCC and functional responses against HBV-infected hepatoma cell lines.

Spinal cord injury (SCI) is associated with severe immunologic changes, such as SCI-induced immune deficiency syndrome, which heightens susceptibility to infections. However, the immune components underlying this immune reorganization remain poorly defined. This study aimed to characterize immune remodeling in patients with SCI across different time points postinjury. High-dimensional flow cytometric profiling was performed on peripheral blood samples from patients with SCI in a cross-sectional observational study to assess immune changes at different postinjury time points. Patients in the subacute phase (22-67 days of postinjury [dpi]) and chronic phase (≥365 dpi) were compared with healthy, sex-matched, and age-matched controls. Alterations in the T-cell and natural killer (NK) cell compartments were observed, particularly in the subacute phase postinjury. Memory T cells and NK cells showed elevated expression of the NAD+ metabolizing enzyme CD38 and immune checkpoint molecules, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), indicating immune activation and possible exhaustion. Coexpression of CD38 and CTLA-4 on T cells was rare, suggesting distinct activation and inhibitory states. In chronic patients, we observed decreased frequencies of NK cells with no substantial changes in T cells and B cells. Notably, changes in CD38, CTLA-4, and PD-1 were no longer found in patients in the chronic phase. These findings reveal noteworthy changes in immune cell activation and exhaustion markers that may contribute to immune vulnerability after SCI, offering novel insights into potential therapeutic targets, such as NAD+ metabolism and immune checkpoint modulation.

TGF-β-mediated suppression of NK cell function and targeting strategies in tumor immunotherapy.