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Specific depletion of TIGIThigh CD226- clonally expanded intratumoral Tregs defines safe and effective TIGIT targeting.
BACKGROUND: Global clinical programs based on TIGIT (T cell immunoglobulin and ITIM domain) blockade have been terminated due to inadequate clinical efficacy. New approaches are needed to increase the antitumor activity of anti-TIGIT-based immunotherapy. METHODS: Multiomics analyses, including single-cell RNA sequencing (scRNA-seq), single-cell TCR sequencing (scTCR-seq), and The Cancer Genome Atlas bulk RNA-seq, were performed to profile TIGIT and the costimulator CD226 expression and assess intratumoral regulatory T cells (Tregs) clonality, with validation by flow cytometry in murine and patient-derived tumor-infiltrating lymphocytes. The therapeutic efficacy of anti-TIGIT antibodies (αTIGIT), including αTIGIT-IgG1-wild-type (WT), αTIGIT-IgG1-WT with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity (αTIGIT-IgG1-ADCC), αTIGIT-IgG4-WT, and tiragolumab, was evaluated in MC38 tumors-inoculated humanized TIGIT knock-in mice (Tigith/h , Tigith/m ). Tumor microenvironment alterations were analyzed using flow cytometry and scRNA/TCR-seq. Antibody binding affinity and ADCC activity were assessed via biolayer interferometry and in vitro ADCC assays. Safety profiles were examined in a murine immune-related adverse events model through growth monitoring, survival analysis, and histopathological evaluation. RESULTS: Using mouse models and clinical sample analysis, we identified a population of TIGIThigh CD226- clonally expanded intratumoral Tregs as a major barrier limiting the ability of TIGIT blockade to enhance effector cell function. αTIGIT-IgG1-ADCC specifically targeted and eliminated the TIGIThigh CD226- clonally expanded Treg subset, resulting in a marked improvement in antitumor efficacy compared with WT and clinically unsuccessful αTIGIT. Mechanistically, removal of these Tregs through αTIGIT-IgG1-ADCC relieved their suppression of stem-like CD4+ T cells, facilitating their differentiation into T helper cell 1 (Th1) effector cells. Th1-derived interferon-gamma (IFN-γ) further enhanced the functionality of tumor-infiltrating CD8+ T cells. Importantly, the presence of clonally expanded intratumoral Tregs and the suppression of stem-like CD4+ T cells correlated with poor immunotherapy response in patients with non-small cell lung cancer. CONCLUSIONS: Targeted elimination of clonally expanded intratumoral Tregs is essential to unlock the full therapeutic potential of αTIGIT. These novel findings provide a key rationale and strategic direction for overcoming the limitations of current αTIGIT-based cancer immunotherapy.
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Acute Inflammation Drives Corneal Pathological Regeneration.
PURPOSE: This study aimed to characterize transcriptional and epigenetic remodeling in the cornea induced by acute inflammation. METHODS: Limbal-corneal tissues were collected on days 5 and 10 after intrastromal administration of lipopolysaccharide or PBS. ScRNA-seq and scATAC-seq were used to delineate the transcriptomic and epigenomic atlas of the inflamed cornea, following the Seurat and Signac pipelines. Immunofluorescence was performed to assess changes in corneal epithelial markers and immune cell infiltration. RESULTS: We identified 16 cell clusters, including ten epithelial cell subpopulations, keratocytes, fibroblasts, corneal endothelial cells, blood vessel cells, lymphatic vessel cells, and immune cells. Lipopolysaccharide induced the infiltration of five major immune cell types: neutrophils, MHC-II⁻ macrophages, MHC-II⁺ macrophages, T cells, and natural killer cells. We characterized gene expression and chromatin accessibility dynamics across all cell types during the inflammatory response, revealing cell-type-specific gene regulatory elements and cis-regulatory chromatin interactions. Regulon activity and motif accessibility analyses identified critical transcription factors that drive distinct inflammatory response programs. Inflammation was found to inhibit limbal stem/progenitor cell differentiation. CellChat analysis revealed a set of secreted intercellular crosstalk signals among all cell types. CONCLUSIONS: Our work provides a comprehensive, time-resolved single-cell transcriptomic and epigenomic atlas of the inflamed cornea, defining cellular functional heterogeneity, cis-regulatory networks, and intercellular communication during corneal pathological regeneration. These findings offer valuable insights into corneal pathology.
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Identification of fatty acid oxidation-related subtypes by integrated analysis of bulk- and single-cell transcriptome profiling in colorectal cancer.
BACKGROUND: As one of the major metabolic reprogramming pathways, fatty acid oxidation (FAO) contributes to rapid progression in tumor cells. Nevertheless, the genomic patterns of patients' FAO levels in colorectal cancer (CRC) remain unknown. Hence, it is crucial to identify the interplay mechanisms of molecular biochemical features of FAO in CRC. METHODS: Data of patients with CRC were accessed from The Cancer Genome Atlas (TCGA). Unsupervised consensus clustering related to FAO sores was conducted. The differentially expressed genes (DEGs) were screened by clustering according to FAO status polarized in TCGA, followed by the construction of the scores of genes related to FAO (GFAO_Score). Enrichment of FAO and carcinogenesis at the cell level were calculated based on the single-cell RNA (scRNA) sequencing analysis. The clinical values and drug analysis of GFAO_Score were evaluated by external validation cohorts from Gene Expression Omnibus (GEO) datasets. RESULTS: We classified patients into two distinct FAO clusters which indicated those with lower FAO levels had poor prognosis and high enrichment of carcinogenic-gene pathways. Further, the high FAO-enriched subtypes in epithelial cells revealed carcinogenesis. Three FAO-related genes (ZFHX4, AQP8, and AKR1B10) were screened to construct the GFAO_Score. The high GFAO_Score group leaned toward advanced CRC and unfavorable survival outcomes in the validation cohort. The low GFAO_Score group possessed a better response to immunotherapy and exhibited lower IC50 (50% inhibition concentration) values for certain chemotherapy drugs, such as 5-fluorouracil, irinotecan, oxaliplatin, paclitaxel, and camptothecin. CONCLUSIONS: FAO patterns vary in patients with CRC. The GFAO_Score might contribute to the precise screening of patients according to metabolism reprogramming and optimization of strategies in clinical practice.
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Retinol-driven Gene Signatures Predict Lung Adenocarcinoma Outcomes and Highlight PAICS as a Therapeutic Opportunity.
UNLABELLED: Retinol, a pivotal regulator of cellular growth and apoptosis, has garnered substantial attention for its intricate involvement in cancer development. To explore Vitamin A's impact on lung adenocarcinoma (LUAD), we utilized comprehensive datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to dissect the intricate role of retinol in cancer progression. The unsupervised clustering analysis, grounded on retinol metabolism gene sets, divided patients into two distinct clusters, with cluster 1 exhibiting significantly inferior survival outcomes. Through differential analysis, we uncovered 349 differentially mutated and 394 differentially expressed genes between these clusters. Leveraging these discoveries, we built a seven-gene signature model that precisely predicted poorer survival for patients with a higher risk score, which was subsequently validated in four independent GEO cohorts, demonstrating its robustness and reliability. Our drug sensitivity analysis further revealed that high-risk patients were more susceptible to gefitinib and erlotinib. Notably, leveraging gene dependency scores and RNA-seq data from LUAD cell lines, we identified Phosphoribosylaminoimidazole Carboxylase And Phosphoribosylaminoimidazolesuccinocarboxamide Synthase (PAICS) as a potential therapeutic target. Single-RNA sequencing confirmed PAICS's predominant expression in cancer cells, and functional assays underscored its oncogenic role in promoting cell proliferation, migration, and invasion. These novel findings offer profound insights into potential therapeutic avenues for LUAD patients with poor prognoses, paving the way for future research endeavors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-025-00223-y.
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TCGA-based identification of prognostic biomarkers and candidate traditional Chinese medicine compounds in papillary thyroid carcinoma: An observational study.
This study aimed to identify prognostic genes associated with papillary thyroid carcinoma (PTC) and explore candidate traditional Chinese medicine (TCM) compounds using integrated bioinformatics and molecular docking. In this observational study, PTC gene expression profiles and clinical data were obtained from The Cancer Genome Atlas. Differentially expressed genes were screened using differential-expression sequencing (DESeq2), followed by protein-protein interaction network analysis to identify hub genes. Their expression, diagnostic value, immune relevance, prognostic significance, protein-level validation, and single-cell distribution were assessed using gene expression profiling interactive analysis, receiver operating characteristic analysis, immune infiltration analysis, Kaplan-Meier survival analysis, the human protein atlas, and single-cell RNA-sequencing data. Candidate TCM compounds were predicted using symptom mapping (SymMap) and the TCM Systems Pharmacology Database and Analysis Platform, and molecular docking was performed to evaluate potential ligand-target interactions. Five hub genes, colony-stimulating factor 2, apolipoprotein E, fibronectin 1 (FN1), collagen type I alpha 1 chain (COL1A1), and intercellular adhesion molecule 1, were identified and found to be significantly upregulated in PTC tissues, with diagnostic value in receiver operating characteristic analysis. Immune infiltration analysis showed associations with macrophages, dendritic cells, and T helper 1 cells, whereas single-cell analysis demonstrated heterogeneous expression across immune and stromal cell populations, including fibroblasts. Higher FN1 and COL1A1 expression was associated with poorer outcomes. Immunohistochemistry supported the expression patterns, while single-cell analysis provided exploratory cell-type-level context for the cellular distribution of selected genes. Ginseng and Smilax glabra were predicted as common candidate TCMs, and docking suggested favorable binding between their active compounds and selected hub targets. Colony-stimulating factor 2, apolipoprotein E, FN1, COL1A1, and intercellular adhesion molecule 1 may be biologically relevant hub genes in PTC, while FN1 and COL1A1 may have prognostic value. Predicted TCM compounds provide preliminary computational evidence for possible compound-target interactions, requiring experimental and clinical validation.
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DCX knockout ferret reveals a neurogenic mechanism in cortical development.
Lissencephaly is a rare brain malformation for which our understanding remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we establish doublecortin (DCX) knockout ferrets as a model that faithfully replicates key features of the disorder. We reveal the critical roles of DCX in neural progenitor cell proliferation and radial glial fiber extension, processes essential for normal cortical development. Utilizing single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics, we provide a detailed atlas of the lissencephalic cortex, illustrating disrupted neuronal lamination and the specific interactions between inhibitory and excitatory neurons. These findings enhance our understanding of the cellular and molecular mechanisms underlying lissencephaly and highlight the potential of DCX knockout ferrets as a valuable tool for neurodevelopmental research, offering insights into both the pathology of lissencephaly and the general principles of brain development.
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Single-cell atlas of photoaged skin reveals JAK-STAT blockade as a strategy to reverse dermal remodeling.
INTRODUCTION: Chronic ultraviolet (UV) exposure superimposes inflammatory and matrix-degenerative insults on intrinsic aging to produce cutaneous photoaging, yet the cell-type-resolved circuits and druggable nodes driving this process remain poorly defined. METHODS: Chronic We established a chronic UVA+UVB-induced mouse model of photoaging and performed single-cell RNA sequencing of control, UV-exposed, and UV + ruxolitinib-treated dorsal skin to map photoaging and therapeutic response at cellular resolution. RESULTS: Chronic Across 14 major lineages, UV exposure preserved overall cellular composition but induced a coordinated transcriptional network shift, marked by activation of JAK-STAT/IRF/AP-1-driven inflammatory and oxidative-stress programs and suppression of developmental, DNA-repair, and differentiation modules. Fibroblast reclustering resolved eight states and identified a papillary-to-reticular transitional continuum with the highest transcriptional burden, integrating senescence-associated secretory phenotype and extracellular-matrix disassembly signatures and skewing pseudotime toward late, terminal states. Topical JAK1/2 inhibition with ruxolitinib attenuated clinical and histological photoaging phenotypes, restored collagen and elastic fiber architecture, and rebalanced fibroblast trajectories by suppressing inflammatory/stress pathways while reactivating basement-membrane, extracellular-matrix, adhesion, and wound-healing programs. Cross-lineage analysis further revealed reversal of conserved stress-metabolic axes, including Hmox1, Gpx3, Ucp2, and Nr4a2, restoration of structural-matrix programs involving Dcn, Gsn, and Nup210l, normalization of aging regulators such as Cdkn1a and Trp53, and re-establishment of dermal-epidermal crosstalk through collagen IV-syndecan and fibronectin/laminin-CD44/αvβ1 signaling. DISCUSSION: Chronic These findings identify transitional fibroblasts as central executors of UV-driven dermal remodeling and support JAK1/2 inhibition as a network-level strategy to restore dermal-epidermal homeostasis in photoaged skin.
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Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes.
BACKGROUND: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. METHODS: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. RESULTS: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. CONCLUSIONS: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.
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Single-nucleus RNA sequencing decodes abnormal cell-collagen communication in a sheep endometrial fibrosis model.
Endometrial fibrosis in sheep reduces reproductive performance with elusive therapeutic targets. The fibrotic endometrium is a complex ecosystem with heterogeneous cells and their interactions. The molecular characterization of key cells and the mechanisms of these interactions are unclear. To uncover the key molecular features of sheep endometrial fibrosis tissue, we used single-nucleus RNA sequencing to profile the transcriptional characterization of sheep endometrial cells from both normal and fibrotic tissues, aiming to clarify the mechanisms of fibrosis development. Histomorphological analysis revealed significant collagen deposition in fibrotic endometrial tissue. The transcription atlas of sheep endometrial cells was created, identifying eight main endometrial cell types. Key findings include the abnormal expression of collagen-related genes in fibrotic cells and the identification of endothelial cells and fibroblasts as major contributors to fibrogenesis with aberrant receptor-ligand interactions involving collagen-related genes. Fibroblasts had a tendency to differentiate into myofibroblasts in fibroblast-mediated fibrosis progression. In vitro experiments demonstrated the role of fibroblasts in fibroblast activation through the PERK/eIF2α/CHOP stress pathway. Additionally, fibrosis disturbs the immune microenvironment. This study highlights that high collagen gene expression in injured endometrial cells leads to abnormal tissue repair and fibrosis, offering valuable insights for understanding endometrial fibrosis at the single-cell level.
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Identification and Validation of T-Cell Exhaustion Signature for Predicting Prognosis and Immune Response in Pancreatic Cancer by Integrated Analysis of Single-Cell and Bulk RNA Sequencing Data.
PURPOSE: Pancreatic cancer (PACA) is one of the most fatal malignancies worldwide. Immunotherapy is largely ineffective in patients with PACA. T-cell exhaustion contributes to immunotherapy resistance. We investigated the prognostic potential of T-cell exhaustion-related genes (TEXGs). METHODS: A single-cell RNA (scRNA) sequencing dataset from Tumor Immune Single-Cell Hub (TISCH) and bulk sequencing datasets from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were used to screen differentially expressed TEXGs. Kaplan-Meier survival, LASSO regression, and univariate/multivariate Cox regression analyses were performed to construct a TEXG risk model. This model was used to predict the prognosis, tumor immune microenvironment, and immunotherapy response. The PACA cohorts from the ICGC and GSE71729 datasets were used to validate the risk model. Pan-cancer expression of SPOCK2 was determined using the TISCH database. RESULTS: A six-gene (SPOCK2, MT1X, LIPH, RARRES3, EMP1, and MEG3) risk model was constructed. Patients with low risk had prolonged survival times in both the training (TCGA-PAAD, n = 178) and validation (ICGC-PACA-CA, ICGC-PAAD-US, and GSE71729, n = 412) datasets. Multivariate Cox regression analysis demonstrated that the risk score was an independent prognostic variable for PACA. High-risk patients correlated with their immunosuppressive status. Immunohistochemical staining confirmed the changes in TEXGs in clinical samples. Moreover, pan-cancer scRNA sequencing datasets from TISCH analysis indicated that SPOCK2 may be a novel marker of exhausted CD8+ T-cells. CONCLUSION: We established and validated a T-cell exhaustion-related prognostic signature for patients with PACA. Moreover, our study suggests that SPOCK2 is a novel marker of exhausted CD8+ T cells.