Search Results (113)

Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody–drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need. Full article

BST2 has emerged as a multifunctional molecule that bridges antiviral defense, membrane architecture, and tumor immunity. Originally characterized as an interferon-inducible restriction factor that tethers virions to the plasma membrane, BST2 is now recognized as an oncogenic driver and immunoregulatory hub in diverse malignancies. In cancer, BST2 expression is frequently upregulated through promoter hypomethylation and transcriptional activation. Functionally, BST2 promotes proliferation, epithelial–mesenchymal transition, anoikis resistance, and chemoresistance, whereas its loss sensitizes tumor cells to proteotoxic and metabolic stresses. Beyond tumor cells, BST2 modulates the tumor microenvironment by promoting M2 macrophage infiltration, dendritic cell exhaustion, and natural killer (NK)-cell resistance, thereby contributing to immune evasion. Elevated BST2 expression correlates with poor prognosis in glioblastoma, breast, nasopharyngeal, and pancreatic cancers, and it serves as a circulating biomarker within small extracellular vesicles. In conclusion, BST2 is a dual-function molecule that integrates oncogenic signaling and immune regulation, making it an attractive diagnostic and therapeutic target for hematological and solid tumors. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article

Leishmaniasis, a neglected tropical disease caused by protozoa of the genus Leishmania, presents a wide clinical spectrum from self-healing cutaneous lesions to life-threatening visceral disease. Its epidemiology and severity vary by geography and species (Old vs. New World), vector biology, and host factors. Pathogenesis reflects a tripartite interplay among parasite, host, and sand fly saliva. Parasite virulence determinants—including lipophosphoglycan, GP63, proteophosphoglycans, and GPI-anchored antigens—facilitate complement evasion, macrophage entry, and suppression of microbicidal pathways. Innate defenses (complement, neutrophils, dendritic cells, NK cells) and PRR signaling (TLRs/NLRs) shape early outcomes, while the balance between Th1-mediated macrophage activation and Th2/regulatory responses dictates clearance versus persistence. Clinically, most infections remain cutaneous; a minority disseminate to mucosa, driven by immunopathology and species traits. Management must be individualized by Leishmania species, lesion burden/site, immune status, geographic region and drug availability. Local therapies (intralesional antimonials, cryo-/thermotherapy) are suitable for limited disease, whereas systemic agents (antimonials, amphotericin B, miltefosine, pentamidine, azoles) are reserved for complex, mucosal, disseminated, or immunosuppressed cases. Drug resistance—via altered uptake/efflux, metabolic rewiring, and genomic plasticity—increased toxicity and treatment failure. Targeting parasite virulence and unique metabolic pathways, improving species-specific diagnostics, and integrating host-directed strategies are priorities to shorten therapy and improve clinical outcomes. Full article

The hypoxic, cold, and high-ultraviolet radiation environments at high altitude pose severe challenges to mammalian immune and metabolic systems. However, little is known about how captive forest musk deer adapt to high-altitude environments and their seasonal variations. This study analyzed peripheral blood transcriptomes of 33 captive forest musk deer (Moschus berezovskii) at high altitude (~3900 m) and low altitude (~1450 m) during autumn-winter and spring-summer seasons. Results revealed comprehensive immune suppression in the high-altitude group during autumn-winter (downregulation of complement system CFB/C2/C3, interferon pathway genes including FLT3, with only natural killer (NK) cell PRKCQ upregulated), coupled with energy-conserving metabolic reprogramming (altered carbohydrate metabolism, inhibited lipid synthesis, fat mobilization, suppressed protein degradation). During spring-summer, neutrophil antimicrobial responses (SLPI/NCF1/ELANE) and humoral immunity (B cell differentiation genes PAX5/RUNX1; class-switch enzyme AICDA) partially recovered while cellular immunity (IL15/B2M) remained suppressed, accompanied by enhanced anabolic metabolism and adipocyte differentiation. Notably, NK cell-mediated cytotoxicity showed selective enhancement despite comprehensive immune suppression, representing an energy-efficient innate defense strategy. This study provides the first characterization of seasonal immune dynamics in a high-altitude cervid species. These findings reveal persistent immune constraints in high-altitude populations and provide theoretical foundations for disease prevention and health management in captive forest musk deer at high altitudes. Full article

Background/Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor with dismal prognosis and limited treatment options. Immunotherapy, including personalized approaches using tumor-infiltrating lymphocytes (TILs) and allogeneic natural (NK) or engineered killer cells (chimeric antigen receptor NK, NK-CAR), and oncolytic viruses (OV), has shown some potential in GBM. Combining different therapeutic strategies may enhance treatment efficacy. Here, we present a xenograft GBM mouse model with multiparametric detection for various immunotherapy research applications. Methods: In a xenograft GBM NOD-Prkdcs scid Il2rgem1/Smoc (NSG) mouse model based on orthotopic transplantation of patient-derived GBM cultures retaining tumor heterogeneity, intravenous and intratumor immunotherapeutic interventions by TIL and OV therapy were performed. Xenograft engraftment was evaluated using intravital MRI; delivery of OV and TILs to the tumor and changes in the tumor and peritumoral space were assessed using intravital confocal microscopy; and metabolic and structural changes in the tumor and peritumoral environment were assessed via fluorescence lifetime imaging microscopy (FLIM) and optical coherence tomography (OCT). The intravital imaging data were compared with the results of preliminary and final histological and immunocytochemical data. Results: Both OV and TILs demonstrated tumor-specific targeting and delivery across the blood–brain barrier. Further, we showed that in this model the xenograft response to both therapeutic treatments can be assessed using FLIM and OCT. Conclusions: Overall, this work presents an optimized mouse model suitable for assessing the effect of combined TIL immunotherapy and OV on GBM in translational studies. Full article

Immunotherapy has demonstrated significant efficacy in colorectal cancer (CRC), but its therapeutic effects remain limited in microsatellite stable (MSS) patients, indicating the critical role of the tumor immune microenvironment (TIME) in regulating immune responses. Lipid rafts, dynamic membrane microdomains enriched in cholesterol and sphingolipids, have emerged as potential targets for TIME remodeling through their integration of immune signal transduction, enrichment of cell death receptors, and regulation of immune cell functionality. This review outlines the pivotal mediating roles of lipid rafts in cellular survival, death, and tumor progression. Specifically, MSS-type CRC exhibits lipid raft structural remodeling driven by dysregulated lipid metabolism, which fosters multiple immune escape mechanisms through exosome-mediated immunosuppressive signaling, promotion of tumor-associated macrophage (TAM) M2 polarization, enhanced infiltration of regulatory T cells (Tregs), and functional exhaustion of effector cells, such as CD8⁺ T cells and NK cells. Finally, we discuss targeted therapeutic strategies based on lipid raft characteristics and CRC molecular profiles, proposing an innovative multidimensional treatment framework combining immune checkpoint inhibitors with lipid raft-targeted interventions and chemoradiotherapy. This approach provides theoretical and strategic support for overcoming CRC immunotherapy resistance and advancing clinical translation. Full article

Pancreatic cancer often goes unnoticed in its early stages because it causes few or no symptoms, leading to late diagnoses and limited treatment options. The main challenges are delayed detection, drug resistance, and the tumor’s complexity, though progress is being made in targeted therapies, immunotherapy, metabolism-based strategies, and early detection methods. Current treatments aim to boost immune responses, extend survival, and improve quality of life. In pancreatic cancer patients, peripheral blood-derived natural killer (NK) cells show reduced numbers, decreased cytotoxic activity, and lower cytokine secretion, which may contribute to tumor growth and spread. NK cell-based immunotherapies have gained attention, with in vitro and mouse studies showing that NK cells can slow the growth of pancreatic tumor stem-like cells and encourage tumor differentiation through cytokines. Preclinical research in humanized mice suggests that NK cell therapies could reduce tumor load and restore immune function. Probiotics are also being studied in preclinical models as a potential adjuvant in therapy to restore immunity, slow tumor growth, and improve outcomes. This review compiles preclinical evidence on the benefits of combining probiotics with NK cell-based treatments for pancreatic cancer. In vitro studies indicate that probiotics can activate immune cells like peripheral blood mononuclear cells (PBMCs), NK cells, T cells, and antigen-presenting cells to help fight tumors. In humanized mouse models, combining probiotics with NK cell therapy has shown promise in reducing tumor burden, restoring immune function, and even reversing tumor-induced bone damage. The exact probiotic formulations and mechanisms are still under study, and clinical trials are in early stages without conclusive results yet. Full article

Natural killer (NK) cells are the main cytotoxic lymphocytes of the natural immune system, which play an important role in tumor immune surveillance and anti-viral response. The surface receptor NKG2D can recognize NKG2D ligands on the surface of tumor or metabolism-stressed cells, thereby activating immune responses and mediating cytotoxicity and anti-tumor activity of NK cells. However, NKG2D-positive NK cells are regulated by metabolites, and play a negative role in metabolic diseases. Various metabolites, including lipids, reactive oxygen species (ROS), glucose and amino acids, regulate NKG2D expression and NK cell activity and decide the immune microenvironment of pathological tissue. Thus, targeted therapies based on NKG2D-positive NK cell have entirely different strategies in the treatment of tumor or metabolic diseases. This article focuses on the metabolic regulation of NKG2D-positive NK cells and their opposite roles in disease progression, including of cancer and metabolic disease. In the future, in-depth studies of the regulatory mechanisms of the NKG2D signaling pathway by metabolites and the optimization of the safety and efficacy of targeted therapeutic strategies will lead to new breakthroughs in the treatment of tumors and metabolic diseases, providing patients with more effective treatment options. Full article

FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations—most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions—are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition. Full article

Background/Objectives: β-Carotene oxygenase-2 (BCO2) is a mitochondrial carotenoid-cleaving enzyme expressed in multiple tissues, including the lungs. While BCO2 regulates carotenoid handling, its role in shaping pulmonary immune architecture and antiviral responses is unknown. We hypothesized that BCO2 deficiency reprograms epithelial–innate circuits and alters antiviral outcomes. Methods: BCO2-knockout (KO) and C57BL/6J wild-type (WT) mice underwent lung single-cell RNA sequencing (scRNA-seq), immunoblotting, and intranasal SARS-CoV-2 challenge to assess cell-type heterogeneity, pathway programs (by gene set variation analysis, GSVA), and antiviral responses. Results: scRNA-seq resolved 14 major lung cell populations with cell-type-specific pathway shifts. Compared with WT, BCO2 KO lungs showed increased conventional dendritic cells and natural killer (NK) cells, with reductions in macrophages, B cells, and endothelial cells. In KO alveolar type II cells, GSVA indicated a stress-adapted metabolic program. Ciliated epithelium exhibited vitamin-K-responsive and axoneme-remodeling signatures with attenuated glucocorticoid and very-low-density lipoprotein remodeling. Innate lymphoid type 2 cells favored fatty acid oxidation and chromatin dynamics with reduced mitochondrial activity. NK cells were biased toward constitutive chemokine/cytokine secretion and counter-inflammatory signaling. Immunoblotting confirmed the elevated level of interferon regulatory factor-3 protein in BCO2-KO lungs. Functionally, BCO2-KO mice had improved outcomes after intranasal SARS-CoV-2 exposure. Conclusions: Loss of BCO2 reconfigures the pulmonary immune landscape and enhances antiviral responsiveness in mice. These findings identify BCO2 as a nutrient-linked enzyme with immunomodulatory impact and highlight cell-state changes as candidate mechanisms for improved antiviral tolerance. Full article

The novel hybrid fish BTB, derived from crossing blunt snout bream (Megalobrama amblycephala, BSB) and topmouth culter (Culter alburnus, TC), exhibits markedly hypoxia tolerance in aquaculture. In this study, hypoxic treatment experiments confirmed that, comparing to its original parent BSB, the tolerance to low oxygen of BTB increased by 20.0%. Furthermore, a comparative analysis of the transcriptome and metabolome was performed using gill tissues from BTB exposed to normoxic and hypoxic conditions. Under hypoxic conditions, BTB displayed adaptive modifications in gill lamellae and hemocytes. Transcriptomic profiling identified 789 differentially expressed genes (DEGs), with 298 upregulated and 491 downregulated, enriched in pathways including apoptosis, NK cell-mediated cytotoxicity, MAPK/TNF/Toll-like receptor signaling, and HIF-1/FoXO signaling pathways. Twelve hypoxia-related candidate genes (egln3, im_7150988, znf395a, hif-1an, mknk2b, pck2, ero1a, igfbp-1a, vhl, bpifcl, egln1a, and ccna1) were screened and validated as potential contributors to hypoxia tolerance. Metabolomics analysis revealed a total of 108 differential metabolites (78 upregulated and 30 downregulated), predominantly linked to Arginine and proline metabolism, Ether lipid metabolism, Arachidonic acid metabolism, and Glycerophospholipid metabolism. Association analysis of transcriptomics and metabolomics revealed that the DEGs and DMs were enriched in the pathways of glycerophospholipid metabolism, ether lipid metabolism, arachidonic acid metabolism, and arginine and proline metabolism. In summary, BTB exhibited relatively high hypoxia tolerance, and 12 candidate genes related to hypoxia tolerance were identified. These findings laid a foundation for further investigation into the mechanisms of hypoxia tolerance improvement in hybrid fish. Full article

B-cell acute lymphoblastic leukemia (B-ALL) is characterized by the abnormal proliferation of B-lineage lymphocytes in the bone marrow (BM). The roles of immune cells within the BM microenvironment remain incompletely understood. Single-cell RNA sequencing (scRNA-seq) provides the potential for groundbreaking insights into the pathogenesis of B-ALL. In this study, scRNA-seq was conducted on BM samples from 17 B-ALL patients (B-ALL cohorts) and 13 healthy controls (HCs). Bioinformatics analyses, including clustering, differential expression, pathway analysis, and gene set variation analysis, systematically identified immune cell types and assessed T-cell prognostic and metabolic heterogeneity. A metabolic-feature-based machine learning model was developed for B-ALL subtyping. Furthermore, T-cell–monocyte interactions, transcription factor (TF) activity, and drug enrichment analyses were performed to identify therapeutic targets. The results indicated significant increases in Pro-B cells, alongside decreases in B cells, NK cells, monocytes, and plasmacytoid dendritic cells (pDCs) among B-ALL patients, suggesting immune dysfunction. Clinical prognosis correlated significantly with the distribution of T-cell subsets. Metabolic heterogeneity categorized patients into four distinct groups (A–D), all exhibiting enhanced major histocompatibility class I (MHC-I)-mediated intercellular communication. The metabolic-based machine learning model achieved precise classification of B-ALL groups. Analysis of TF activity underscored the critical roles of MYC, STAT3, and TCF7 within the B-ALL immunometabolic network. Drug targeting studies revealed that dorlimomab aritox and palbociclib specifically target dysregulation in ribosomal and CDK4/6 pathways, offering novel therapeutic avenues. This study elucidates immunometabolic dysregulation in B-ALL, characterized by altered cellular composition, metabolic disturbances, and abnormal cellular interactions. Key TFs were identified, and targeted drug profiles were established, demonstrating the significant clinical potential of integrating immunological mechanisms with metabolic regulation for the treatment of B-ALL. Full article

SIRT1-SREBP−1c/PGC−1α signaling is involved in the production of non-esterified fatty acids (NEFAs) and liver lipid metabolism disorders in ketotic calf. The molecules contained in extracellular vesicles (EVs) regulate intercellular communication, and research on calf hepatocytes−derived EVs has become a hot spot. We hypothesized that EVs in cell culture supernatants could affect lipid metabolism in hepatocyte models via SIRT1/SREBP−1c/PGC−1α signaling. Non-ketosis (NK, 0 mM NEFA) and clinical ketosis calf models (CK, 2.4 mM NEFAs) were established in vitro cultured calf hepatocytes and EVs were extracted from their supernatants as NK−derived EVs and CK−derived EVs, respectively. In vitro hepatocyte models, comprising a normal culture group (normal) and the group treated with NEFAs at 2.4 mM (2.4 NEFA), were treated with NK and CK−derived EVs. In addition, we transfected an SIRT1−overexpressing adenovirus into calf hepatocytes and determined the expression of key genes, enzymes, and proteins involved in the SIRT1/SREBP−1c/PGC−1α pathway. The results showed that the NK−derived EVs inhibited the expression of the SREBP−1c gene and protein and increased the expression of the SIRT1 and PGC−1α genes and proteins (p < 0.05). In contrast, CK−derived EVs induced lipid metabolism disorders in the normal hepatocyte group and aggravated NEFA-induced lipid metabolism imbalances in hepatocytes (p < 0.05). Moreover, overexpression of SIRT1 confirmed that EVs exert vital functions in hepatocyte lipid metabolism via SIRT1/SREBP−1c/PGC−1α signaling to regulate hepatocyte lipid metabolism. In summary, NK−derived EVs alleviated liver lipid metabolism disorders caused by NEFAs via modulation of SIRT1/SREBP−1c/PGC−1α signaling, while CK−derived EVs had the opposite effect. NK−derived EVs upregulated lipid oxidation-related genes and downregulated lipid synthesis-related genes, suggesting that NK−derived EVs could be used as biological extracts to alleviate lipid metabolism disorders in ketotic calf. Full article

Background: Both lipid metabolism disorders and inflammation are critical contributors to the progression of metabolic-associated fatty liver disease (MAFLD), yet integrated analyses identifying key genes linking them remain scarce. Methods: Differentially expressed genes in MAFLD were extracted from the GSE135251 dataset and intersected with lipid metabolism- and inflammation-related genes from Molecular Signatures Database (MSigDB). Machine learning on GSE135251, followed by validation on GSE89632, identified key genes. Functional enrichment, immune microenvironment profiling, and nomogram analysis were subsequently conducted. Cellular heterogeneity was assessed using the single-cell sequencing (scRNA-seq) dataset GSE186328, and gene expression in MAFLD mice was validated via real-time Polymerase Chain Reaction (PCR). Activators targeting these genes were predicted using Drug Signatures Database (DsigDB). Results: Four genes—FADS1, FADS2, GLB1, and PNPLA3—were identified as key regulators involved in both lipid metabolism disorders and inflammation in MAFLD. These genes were co-enriched in ribosome-related pathways. GLB1 correlated strongly with CD56dim natural killer cells in immune infiltration analysis. A diagnostic nomogram integrating these genes demonstrated exceptional discriminatory power, with Area Under the Curve (AUC) values of 0.98981 for GSE135251 and 0.9204 for GSE89632. ScRNA-seq revealed elevated FADS1, FADS2, and GLB1 expression in MAFLD-associated NK/T cells compared to controls. Real-time PCR confirmed significant upregulation of all four genes in MAFLD mice. Drug prediction identified estradiol as a potential activator targeting these genes. Conclusions: This study identified FADS1, FADS2, GLB1, and PNPLA3 as key genes involved in the progression of MAFLD, linking metabolic dysfunction and inflammation. Full article