Cathepsin D regulated enalapril effects in distal nephron injury states of diabetic kidney disease. Enalapril reduced proinflammatory triggering receptor expressed on myeloid cells 2+ macrophages interacting with distal nephron cells. Enalapril-associated gene signatures stratified human kidneys by fibrosis and function outcomes. Diabetic kidney disease is the leading cause of kidney failure worldwide. Renin-angiotensin-aldosterone system inhibitors, such as enalapril, have been used for decades as antiproteinuric, antihypertensive, and kidney-protective agents. Still, the exact cell type of action and the molecular mechanism of drug action are elusive. Previous work has primarily emphasized injury patterns in the proximal nephron, leaving potential contributions of other nephron segments insufficiently characterized. Here, we leveraged state-of-the-art single-cell transcriptomics in the Zucker spontaneously hypertensive fatty obese rat to elucidate potential target cells and driver molecules exerting enalapril drug effects. We identified injured cell states of the distal nephron in the context of prolonged enalapril treatment. We showed cathepsin D, a tissue renin-angiotensin-aldosterone system effector, as an important regulator of enalapril effects and revealed triggering receptor expressed on myeloid cells 2+ residential macrophages as top receivers of distal nephron-derived signals. Finally, we showed that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures such as kidney function and fibrosis. We reported cathepsin D as an important regulator of enalapril effects, involving cross-talk between the distal nephron and triggering receptor expressed on myeloid cells 2+ residential macrophages. We also demonstrated that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures.

Myeloid cells-including macrophages, monocytes, neutrophils and dendritic cells-are metabolically plastic sentinels that shape the tumor microenvironment. Among the myriad metabolites in cancer, lactate and nicotinamide adenine dinucleotide (NAD⁺) stand out as central coordinators of myeloid cell fate. Lactate accumulation, driven by tumor glycolysis, profoundly reprograms myeloid metabolism through receptor-mediated signaling, monocarboxylate transport and histone lactylation, establishing immunosuppressive and pro-angiogenic phenotypes. Parallel to this, the nicotinamide phosphoribosyltransferase (NAMPT)-dependent NAD⁺ salvage pathway sustains redox homeostasis and epigenetic regulation in myeloid cells, controlling sirtuin-mediated deacetylation and transcriptional rewiring. Emerging evidence suggests a lactate-NAMPT feedback circuit that couples extracellular lactate availability with intracellular NAD⁺ turnover to maintain immunoregulatory states within tumors. In this Review, we integrate current knowledge on lactate metabolism and NAMPT signaling in tumor-associated myeloid cells, highlighting their convergence on metabolic and epigenetic checkpoints. We further discuss how artificial intelligence (AI)-through single-cell multi-omics integration, spatial metabolomic inference and graph-based modeling-can decode complex immunometabolic networks and accelerate drug discovery targeting these pathways. Finally, we outline therapeutic strategies combining lactate-targeting agents, NAMPT inhibitors and immunotherapies, emphasizing the promise of AI-guided precision immunometabolism. Understanding and modeling the lactate-NAMPT axis may unlock new avenues to reprogram myeloid immunity and overcome resistance in cancer therapy.

Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice.

Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in many hematologic malignancies, but success in relapsed/refractory (R/R) acute myeloid leukemia (AML) has been limited due to underwhelming response rates and high on-target/off-tumor toxicity. This phase 1 dose-escalation trial evaluated the safety and efficacy of KITE-222, an autologous CAR T-cell therapy that recognizes C-type lectin-like molecule 1 (CLL-1), predominantly expressed on myeloid cells but absent on normal hematopoietic stem cells and other tissues. Patients with R/R AML (≥50 kg) received a single intravenous infusion of 3 × 107 (cohort 1), 1 × 108 (cohort 2), or 3 × 108 (cohort 3) KITE-222 CAR+ T cells. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Key secondary endpoints included overall remission rate, incidence of adverse events (AE), and pharmacokinetics/pharmacodynamics. Twelve patients received KITE-222. One patient in cohort 3, who was the only patient to receive two courses of lymphodepleting chemotherapy, experienced a DLT (prolonged grade 4 neutropenia/thrombocytopenia) but achieved a best response of morphologic leukemia-free state on day 14 following infusion (confirmed on day 44). All patients experienced grade ≥3 AEs, none had grade ≥3 cytokine release syndrome, and one had grade ≥3 immune effector cell-associated neurotoxicity syndrome. Clinically meaningful responses were lacking across dose levels despite detectable CAR T-cell expansion. Although two of five cohort 3 patients with clear expansion had near-complete depletion of CLL-1+ bone marrow blasts after infusion, CLL-1- blasts persisted, and reductions in total blasts were not observed. Despite successful manufacturing and acceptable safety, KITE-222 lacked preliminary efficacy, warranting future studies that address CLL-1 heterogeneity and focus on improving in vivo expansion and antitumor activity.

The purpose of this study was to explore the composition and function of immune cell subsets at the single-cell level in the thymus and peripheral blood of patients with myasthenia gravis (MG). A total of 9701 and 23 846 cells, respectively, originated from the peripheral blood and thymus samples of two MG patients, and 6930 cells from the peripheral blood of two gender- and age-matched healthy controls (HCs) were selected for single-cell RNA-sequencing. Uniform manifold approximation and projection (UMAP), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Monocle3, and Velcyto were performed to analyze the composition, molecular and functional properties, and developmental trajectory of immune cell subsets. Four major cell populations of T cells, B cells, myeloid cells, and natural killer cells were identified, as well as their 15 cell subpopulations. An absolute predominance of T cells was found in the thymus and peripheral blood of MG patients, and the proportions of memory B cells in both plasma and thymus showed an increasing trend while the number of naïve B cells demonstrated a decreasing trend in MG patients compared with HCs. Besides, the monocytes in the peripheral blood of MG patients had the strongest interactions with other cells. Furthermore, CXCL, GAS, and CD30 signaling pathways were more enriched within MG peripheral blood. Our research clarifies the cellular heterogeneity in the pathogenesis of MG and characterizes the immune microenvironment of thymic tissues in MG patients.

Liver ischemia-reperfusion injury (IRI) is a sterile inflammatory process that contributes significantly to graft rejection following liver transplantation. Although SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is known to preserve genomic stability and restrain inflammation under oxidative stress, its immunoregulatory function in myeloid cells during liver IRI has not been elucidated. This study aimed to investigate the role and mechanism of SETDB1 in regulating macrophage-driven inflammatory responses in liver IRI. Myeloid-specific SETDB1 knockout (SETDB1 cKO) mice exhibited exacerbated liver injury, increased infiltration of pro-inflammatory macrophages and neutrophils, and amplified inflammatory responses compared with SETDB1fl/fl controls. Depletion of macrophages alleviated liver damage, reduced neutrophil infiltration and hepatocyte apoptosis, and eliminated the excessive injury observed in SETDB1 cKO mice. Mechanistically, SETDB1 suppressed the expression of purinergic receptor P2X7 (P2RX7). Pharmacological inhibition of P2RX7 with oxidized adenosine triphosphate significantly attenuated liver injury and macrophage infiltration in SETDB1 cKO mice. In vitro assays confirmed that SETDB1 inhibited the P2RX7/Caspase-1/Gasdermin D (GSDMD) pathway in macrophages, thereby limiting pyroptosis and inflammation. This study identifies SETDB1 as a previously unrecognized regulator of macrophage pyroptosis during liver IRI. By linking epigenetic regulation to suppression of the P2RX7/Caspase-1/GSDMD pathway, our findings provide novel mechanistic insight into how SETDB1 protects against sterile liver inflammation. SETDB1 plays a pivotal role in protecting the liver from IRI by restraining macrophage-mediated pyroptosis and inflammation. These findings suggest that targeting the SETDB1/P2RX7/Caspase-1/GSDMD axis may represent a promising therapeutic strategy for mitigating liver IRI and improving transplant outcomes. Antioxid. Redox Signal. 45, 133-148.

Basal cell carcinomas (BCCs) are thought to reside within an immunosuppressed tumor microenvironment, but a detailed characterization of BCC-associated immune cells was lacking. Utilizing multiplex immunohistochemistry (IHC) (Vectra Polaris, Akoya Biosciences), we designed two staining panels, targeting either T cells (CD3, CD4, CD8, FoxP3, PD1) or myeloid cells (neutrophil elastase, CD68, CD163, HLADR, CD1c). Formalin-fixed paraffin-embedded (FFPE) BCC tumor specimens (n = 30) were analyzed using the panels. The majority of immune cells reside at the peritumoral margin; therefore, a boundary zone of 150 μm around tumor nests was used to capture them. A CD8/T-reg ratio and M1/M2 macrophage ratio of < 0.5 was observed across all BCC specimens, confirming an overall immunosuppressive phenotype. Among different histologic subtypes, infiltrative BCC had significantly lower CD8 T cells (p = 0.038), T-regulatory cells (p = 0.039), and CD8/T-reg ratio (p = 0.048), as well as lower M1/M2 ratio (p = 0.034) compared to non-infiltrative BCC subtypes. The association of infiltrative BCC with a more immunosuppressed microenvironment may contribute to more aggressive biological behavior. Overall, these data demonstrate a method to determine T cell and myeloid profiles in fixed FFPE skin tumor tissues that can identify subtle immune profile differences.

Iron, autoimmunity, and thrombosis: Exploring sex-specific interactions.

TREM2 as a possible link between Alzheimer's disease and diabetes mellitus.

Transcriptomic sequencing analysis of the tumor microenvironment atlas and potential mechanisms of metastasis in papillary thyroid carcinoma.

Targeting TREM2 to disentangle neuroinflammation and α-Syn pathological propagation in Parkinson's disease.

BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid metabolism remains unclear.ObjectiveTo investigate the association between plasma sTREM2 and peripheral lipid profiles in AD and to explore the mechanistic role of TREM2 in peripheral lipid regulation.MethodsWe conducted a cross-sectional study of 59 AD patients and 54 healthy controls and measured plasma biomarkers including sTREM2 as well as performed targeted lipidomics profiling. Mechanistic exploration was performed via plasma and hippocampal lipidomics in Trem2 knockout and APP/PS1 mice.ResultsPlasma sTREM2 levels were elevated in AD and were negatively correlated with the plasma p-tau217/Aβ42 ratio and p-tau217. Multivariate analysis revealed a distinct lipidomics signature in AD, in which 30 lipid species were significantly altered. We prioritized significantly altered biomarkers to inform a composite biomarker panel combining sTREM2 with a set of sphingomyelins, phosphatidylinositols, diacylglycerols, fatty acids, and cholesteryl esters, which showed strong discrimination between AD and controls (AUC = 0.93). In a mouse model of APP/PS1, we found that Trem2 knockout partially normalized plasma sphingomyelins and hexosylceramide levels. Finally, cross-tissue comparisons further suggested that TREM2 exerted distinct effects on peripheral sphingolipid metabolism that were less evident in hippocampal tissue.ConclusionsOur findings associate TREM2 with lipid dysregulation in AD and support development of a plasma sTREM2-lipid panel for patient classification.

Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

Protein 4.1R regulates CCDC26 and impacts myeloid leukemia progression.

Acute promyelocytic leukemia (APL) has been treated for decades with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), which achieve excellent survival but remain limited by induction mortality, ATO-related toxicities, and relapse in some patients. Src family kinases (SFKs) regulate proliferation and survival of myeloid lineage cells, and SFK inhibition has been reported to enhance retinoic acid (RA)-induced differentiation. We investigated whether clinically available SFK inhibitors can augment ATRA-induced differentiation of APL-derived NB4 cells more effectively than the ATRA plus ATO standard regimen. NB4 cells were treated with PP2, bosutinib, or dasatinib with or without ATRA. Differentiation was assessed by CD11b expression using flow cytometry and by nitroblue tetrazolium reduction. SFK phosphorylation and retinoic acid receptor (RAR) target gene expression were evaluated by immunoblotting. Apoptosis was analyzed to distinguish differentiation from cytotoxic effects. ATRA plus ATO modestly increased CD11b-positive cells (17.4%±1.7), whereas ATRA combined with PP2, bosutinib, or dasatinib yielded 49.5%±5.3, 31.4%±2.1, and 53.2%±2.3 CD11b-positive cells, respectively, all significantly higher than ATRA plus ATO (p<0.05). Enhanced granulocytic differentiation was confirmed by nitroblue tetrazolium reduction and was not accompanied by increased apoptosis. SFK inhibitors reduced SFK phosphorylation and increased RAR target protein expression in parallel with augmented differentiation. Clinically available SFK inhibitors, particularly dasatinib, synergistically enhance ATRA-induced myeloid differentiation of NB4 APL cells and are more effective than the conventional ATRA plus ATO combination in this in vitro model. These findings support further preclinical and clinical evaluation of SFK inhibitor plus ATRA combinations as differentiation-oriented strategies and potential alternatives or complements to ATO-containing regimens in APL.

Thyroid cancer exhibits substantial heterogeneity in its tumor immune microenvironment (TIME), which critically shapes disease progression and therapeutic responsiveness. While most differentiated thyroid cancers (DTCs) remain indolent, a subset evolves into radioiodine-refractory disease or progresses to poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC), characterized by aggressive behavior and limited treatment options. Emerging evidence suggests that this transition is accompanied by dynamic immune reprogramming rather than static immune evasion. In this review, we propose a stepwise model of immune evolution in thyroid cancer, spanning from autoimmune-driven inflammation in chronic lymphocytic thyroiditis (CLT) to immune-exhausted states in advanced tumors. We systematically characterize immune cell composition, functional states, and regulatory networks across disease stages, highlighting key shifts in antigen presentation, T-cell functionality, and myeloid cell polarization. Building on this framework, we integrate tumor immune phenotypes (“hot”, “altered”, and “cold”) with actionable biomarkers, including PD-L1 expression, tumor mutational burden, IFN-γ signatures, M2 macrophage-related signature, and tertiary lymphoid structures. We further map these immune contexts to rational therapeutic strategies, encompassing immune checkpoint blockade, combination regimens with tyrosine kinase inhibitors or radiotherapy, and emerging approaches such as innate immune activation and adoptive cell therapies. By linking immune evolution with therapeutic vulnerabilities, this review provides a translationally relevant framework for precision immunotherapy in thyroid cancer and highlights future directions for overcoming resistance in advanced disease.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by enhancing antitumor immunity but are associated with immune-related adverse events, including myocarditis. Although T cell involvement in ICI-associated myocarditis is well established, the contribution of myeloid-specific programmed death-ligand 1 (PD-L1) signaling to cardiac immune regulation remains unclear. To investigate the role of myeloid-specific PD-L1 in maintaining cardiac immune homeostasis, we generated a myeloid-specific PD-L1 conditional knockout (KO) mouse model using LysMCre-driven deletion. Cardiac function was assessed by echocardiography. Immune profiling of cardiac and systemic compartments was performed using flow cytometry, quantitative PCR, ELISA, and histological analyses. In vitro coculture assays were conducted to assess macrophage-fibroblast (FB) and macrophage-T cell interactions. Myeloid PD-L1 KO mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction, left ventricular fractional shortening, and upregulated heart failure markers. Immune profiling revealed systemic and myocardial inflammation, with increased C-C chemokine receptor type 2 macrophages and activated T cells. Coculture assays confirmed that PD-L1-deficient myeloid cells enhance T cell activation, Th17 polarization, and FB-mediated fibrotic gene expression. Myeloid-specific PD-L1 plays a critical role in limiting inflammation and maintaining cardiac integrity. Its deficiency promotes a proinflammatory microenvironment, contributing to cardiac dysfunction and implicating it as a key player in ICI-associated myocarditis. These findings identify myeloid PD-L1 as a potential therapeutic target to mitigate immune-mediated cardiotoxicity.NEW & NOTEWORTHY Immune checkpoint inhibitor-associated myocarditis is incompletely understood beyond T cell-driven mechanisms. This study identifies myeloid-specific PD-L1 as a critical regulator of cardiac immune homeostasis. Loss of myeloid PD-L1 triggers early myocardial inflammation, immune cell infiltration, FB activation, and subsequent cardiac dysfunction. These findings uncover a previously unrecognized myeloid checkpoint pathway contributing to immune-mediated cardiotoxicity and highlight myeloid PD-L1 as a potential therapeutic target.

A novel microtubule inhibitor modulates the myeloid PD-L1 expression, restores T cell effector function, and promotes apoptosis for effective suppression of colorectal cancer.

To further understand the mechanism of action of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with systemic lupus erythematosus (SLE) in the phase 2 PAISLEY SLE trial. RNA sequencing (RNA-seq) was performed on samples collected from baseline to week 32 in 363 patients and 56 healthy volunteers. Pharmacodynamics of differentially expressed genes (DEGs) were analysed with linear mixed-effects models using the statistical software package DREAM (differential expression for repeated measures). Single-sample gene set enrichment analysis (ssGSEA) was performed using MSigDB Hallmark and BloodGen3 gene modules. The xCell R package was used to digitally portray the blood cellular heterogeneity landscape. At baseline, 527 DEGs were identified in patients with SLE vs healthy volunteers (log2 fold change >1; adjusted P < .05). Deucravacitinib modulated up to 2529 genes and SLE-relevant gene sets, including interferon-regulated genes. ssGSEA showed that plasma cell gene sets decreased and myeloid cell gene sets reverted towards normal levels with deucravacitinib; xCell deconvolution revealed significant enrichment of dendritic cell populations with deucravacitinib vs placebo. At baseline, regulatory T-cell gene sets were increased in patients with SLE vs healthy volunteers and further increased with deucravacitinib. There were some variable, dose-dependent increases in naïve and memory B lymphocytes. Whole blood transcriptome profiling via RNA-seq revealed both expected and novel gene expression changes with deucravacitinib across multiple pathogenic pathways. These data demonstrate successful targeting of pathophysiologic immune mechanisms that should be validated in future studies and support continued evaluation of deucravacitinib in the phase 3 POETYK SLE trials.

Glioblastoma is the most lethal primary brain tumor, characterized by a profoundly immunosuppressive microenvironment. This stroma includes various immunosuppressive and tumor-killing cells. This review critically evaluates emerging strategies for reprogramming the glioblastoma microenvironment to restore antitumor immunity. We focus on novel small molecules, natural products, adjuvants, and nanomedicine platforms that can remodel immunosuppressive microenvironment of glioblastoma. Preclinical studies demonstrate that therapy modalities can induce various forms of cell death and the release of danger signals that not only stimulate immunogenic responses but also cause the regulation of checkpoint molecules. In addition, several cytokines and danger signals can stimulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor of κappa B (NF‑κB) in cancer and immune cells. These factors not only enhance resistance to apoptosis but also boost immunosuppressive responses. Targeting cancer-associated fibroblasts (CAFs) and their specific secretions, reprogramming marcrophages using colony-stimulating factor-1 (CSF-1) inhibitors or toll-like receptor (TLR) agonists, depleting myeloid cells through chemokine receptor blockade, and disrupting metabolic suppression can each partially remodel glioblastoma microenvironment. Nanocomplexes improve brain delivery and enable multimodal drug co-delivery. However, clinical translation has been disappointing for checkpoint inhibitors in phase III trials. Furthermore, myeloid-targeted agents have shown limited efficacy because of the profound plasticity and redundancy of the glioblastoma microenvironment. Effective immunotherapy for glioblastoma will require rationally designed multimodal combinations that simultaneously target the stromal barriers, the immunosuppressive milieu, and the exhausted state of T cells. Emerging strategies such as oncolytic viruses engineered to express immunomodulatory payloads and biomarker-guided adaptive trial designs can be promising for future studies.