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Single-cell RNA sequencing highlights the immunosuppression of IDO1+ macrophages in the malignant transformation of oral leukoplakia.
Rationale: Immunosuppressive tumor microenvironment (iTME) plays an important role in carcinogenesis, and some macrophage subsets are associated with iTME generation. However, the sub-population characterization of macrophages in oral carcinogenesis remains largely unclear. Here, we investigated the immunosuppressive status with focus on function of a macrophage subset that expressed indoleamine 2,3 dioxygenase 1 (Macro-IDO1) in oral carcinogenesis. Methods: We built a single cell transcriptome atlas from 3 patients simultaneously containing oral squamous cell carcinoma (OSCC), precancerous oral leukoplakia (preca-OLK) and paracancerous tissue (PCA). Through single-cell RNA sequencing and further validation using multicolor immunofluorescence staining and the in vitro/in vivo experiments, the immunosuppressive cell profiles were built and the role of a macrophage subset that expressed indoleamine 2,3 dioxygenase 1 (Macro-IDO1) in the malignant transformation of oral leukoplakia was evaluated. Results: The iTME formed at preca-OLK stage, as evidenced by increased exhausted T cells, Tregs and some special subsets of macrophages and fibroblasts. Macro-IDO1 was predominantly enriched in preca-OLK and OSCC, distributed near exhausted T cells and possessed tumor associated macrophage transformation potentials. Functional analysis revealed the established immunosuppressive role of Macro-IDO1 in preca-OLK and OSCC: enriching the immunosuppression related genes; having an established level of immune checkpoint score; exerting strong immunosuppressive interaction with T cells; positively correlating with the CD8-exhausted. The immunosuppression related gene expression of macrophages also increased in preca-OLK/OSCC compared to PCA. The use of the IDO1 inhibitor reduced 4NQO induced oral carcinogenesis in mice. Mechanistically, IFN-γ-JAK-STAT pathway was associated with IDO1 upregulation in OLK and OSCC. Conclusions: These results highlight that Macro-IDO1-enriched in preca-OLK possesses a strong immunosuppressive role and contributes to oral carcinogenesis, providing a potential target for preventing precancerous legions from transformation into OSCC.
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Identification of prognosis and therapy related intratumoral microbiome and immune signatures in gastric cancer.
The impact of the intratumoral microbiome (ITM) on the treatment and prognosis of gastric cancer (GC) remains controversial. Our study analyzed the differential ITM in GC tissues and identified nine bacterial genera significantly associated with overall survival (OS), with seven as risk factors and two as protective factors. Three distinct clusters with varying survival outcomes were defined, demonstrating correlations with pathological stage and immune features. An immune-related gene-based RiskScore model incorporating genes such as Apolipoprotein D (APOD), Stanniocalcin 1 (STC1), Coagulation Factor II Thrombin Receptor (F2R), Angiotensinogen (AGT), Fatty Acid Binding Protein 4 (FABP4), Inhibin Subunit Beta A (INHBA), Caspase Recruitment Domain Family Member 11 (CARD11), and Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) was established and validated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. When combined with clinical factors, this RiskScore model formed a Nomogram model achieving Areas Under the Curve (AUCs) of 0.72, 0.76, and 0.79 for 1, 3, and 5-year OS predictions, respectively. This model exhibited robust predictive accuracy over time and correlated with mutation frequency, drug sensitivity, and immunotherapy response. Furthermore, single-cell analysis revealed that tumor-associated fibroblasts may play a pivotal role in immune-microbial interactions. The results were confirmed using quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry (IHC). In conclusion, the prognostic model incorporating ITM and immune-related genes aids in risk stratification and provides valuable insights and targets for GC treatment.
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A spatiotemporal atlas of cholestatic injury and repair in mice.
Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFβ in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.
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TIM-3/CD68 double-high expression in Glioma: Prognostic characteristics and potential therapeutic approaches.
BACKGROUND: Immunotherapy has revolutionized the treatment of various types of tumors, but there has been no breakthrough in the treatment of gliomas. The aim of this study is to discover valuable immunotherapy target in glioma, analyze its expression in glioma and the related microenvironment, explore potential immunotherapy strategies, and propose new possibilities for the treatment of gliomas. METHODS: Immunohistochemistry (IHC) and multiplex fluorescence immunohistochemistry (mIHC) were used to analyze the expression of common immune markers and checkpoints in 187 glioma patients from Sun Yat-sen University Caner Center (SYSUCC). Bioinformatics analysis was used to examine the expression of TIM-3 in different macrophages using the Chinese Glioma Genome Atlas (CGGA) single-cell sequencing database. The Kaplan-Meier curve was used to predict the prognostic value of samples with high TIM-3 and CD68 expression. The R package was used to analyze the somatic mutation status and the sensitivity of small molecule inhibitors in TIM-3/CD68 double-high expression samples. RESULTS: TIM-3 is a relatively highly expressed immune checkpoint in glioma. Unlike other tumors, TIM-3 is mainly expressed on macrophages in the glioma microenvironment. TIM-3/CD68 double-high expression suggests poor survival in glioma and may be a new upgrade marker in both IDH-mutant glioma and IDH-wildtype low-grade glioma (LGG) glioma (P < 0.01). Exploring the combination of TIM-3 inhibitors and p38 MAPK inhibitor may be a potential treatment direction for TIM-3/CD68 double high expression gliomas in the future. CONCLUSIONS: The combination of TIM-3 and CD68 holds significant importance as a potential target for both prognosis and therapeutic intervention in glioma.
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Identification of prognostic biomarkers and immunotherapy response predictors in lung adenocarcinoma: integrative Mendelian randomization and machine learning analysis.
BACKGROUND: Lung adenocarcinoma (LUAD), the most prevalent and clinically heterogeneous form of lung cancer, lacks robust biomarkers for prognosis and immunotherapy response prediction. This study aimed to identify key prognostic genes and develop a predictive framework to guide personalized treatment strategies. METHODS: We integrated summary data-based Mendelian randomization (SMR) with machine learning to identify LUAD-associated genes. RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed. A prognostic model was constructed with 101 combinations of 10 machine learning algorithms and validated via receiver operating characteristic (ROC) curve and concordance index analyses. Single-cell RNA-sequencing and spatial transcriptomic data were further examined to clarify the therapeutic implications of the identified genes. RESULTS: SMR identified 316 LUAD-associated genes, among which 33 were associated with prognosis according to univariate Cox regression. The optimal model combining random survival forest and ridge regression achieved superior predictive accuracy, with the area under the curves for 1-, 3-, and 5-year survival being 0.757, 0.707, and 0.686, respectively. High-risk patients exhibited distinct immune microenvironment suppression, reduced tumor mutation burden, and diminished immunotherapy responsiveness as compared to their low-risk counterparts. Single-cell and spatial transcriptomic analyses identified interactions between cancer cells and stromal cells as potential therapeutic targets. CONCLUSIONS: The integrative approach employed in this study identified prognostic biomarkers and immunotherapy response predictors for patients with LUAD, offering a machine learning-driven framework for risk stratification and precision oncology. The findings underscore the clinical utility of combining genetic epidemiology with advanced analytics to optimize therapeutic strategies.
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HPV Infection Drives CXCL8+ Neutrophil-Mediated Immune Suppression in Cervical Cancer.
Persistent HPV infection is a major risk factor for cervical cancer, but the immune mechanisms behind HPV-induced tumor progression are not fully understood. Neutrophils may play a key role in immune remodeling and evasion within the HPV-infected tumor microenvironment. We integrated 31 cervical samples (including HPV-infected and non-infected normal, tumor, and HSIL tissues) to construct a single-cell atlas of 141,785 cells. Neutrophil heterogeneity, cell-cell communication, and immunosuppressive programs were systematically analyzed. Transcriptomic findings were validated via immunohistochemistry, immunofluorescence, and Mendelian randomization (MR). HPV infection dramatically remodeled the immune landscape, inducing robust neutrophil and plasma cell infiltration while reducing T cell abundance. Neutrophils in HPV+ tissues were terminally differentiated and displayed a distinct CXCL8+ phenotype. These CXCL8+ neutrophils were identified as late-stage, transcriptionally defined low-plasticity state enriched with immunosuppressive genes (e.g., SPP1, VEGFA). They exhibited enhanced interactions with T cell subsets, particularly regulatory and cytotoxic T cells, via ligands like CXCL16 and APOE, suggesting direct immunosuppressive crosstalk. MR analysis indicated a causal role for CXCL8 in cervical cancer, and spatial protein assays confirmed elevated CXCL8 and its receptor CSF3R in HPV+ tumors. HPV infection expands immunosuppressive CXCL8+ neutrophils that modulate T cell activity and promote immune escape. CXCL8 is identified as a causal factor and potential therapeutic target in HPV-driven cervical cancer.
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A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions.
Demyelinating diseases, including multiple sclerosis (MS), are characterized by loss of myelin and progressive neurodegeneration. It remains unclear if demyelination mouse models, such as cuprizone (CPZ) and lysophosphatidylcholine (LPC) elicit distinct responses or are comparable to human disease. Here, we integrate new and published single-cell transcriptomic datasets from CPZ- and LPC-induced demyelination and compare them with human MS data. We find that CPZ induces a distinct, stressed oligodendrocyte (OL) state, marked by Cdkn1a and Nupr1, that resembles phenotypes in MS lesions. The models converge on an immune responsive OL state expressing Socs3, B2m, and interferon-response genes during remyelination. Mouse microglia share a conserved activation program, although LPC drives a stronger, prolonged response. However, neither model captures the oligodendrocyte progenitor and microglial heterogeneity observed in MS. These results provide a cross-model, cross-species atlas of glial states and offer a framework to strategically leverage mouse models to study myelin injury and repair.
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Molecular heterogeneity of the non-human primate cochlea.
Unraveling the intricate composition and function of the cochlea is paramount to comprehending the mechanisms underlying sound perception and the pathogenesis of auditory disorders. The mammalian cochlea displays a highly organized structure, which contributes to the diversity and complexity of auditory processing. However, the cellular intricacies in non-human primates remain largely unexplored. In the present study, we employed high-throughput transcriptomic sequencing to profile over 36,701 nuclei across virtually all cochlear cell types in both juvenile and adult Macaca fascicularis at single-cell resolution. Our analysis unveiled remarkable heterogeneity both across and within cell types. Despite a largely conserved cellular composition of the cochlea between mouse and macaque species, glial cells exhibited substantial species-specific diversity, while hair cells and spiral ganglion neurons with specialized transcriptional programs were well-mapped onto their murine counterparts, underscoring the similarities that persist despite evolutionary divergence. Furthermore, we constructed a disease map associated with hearing loss, establishing this transcriptomic atlas of the macaque cochlea as an indispensable resource for future investigations in both human and non-human primates.
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Müller Glia Subtypes Define Neuro-Glial Associations and Spatial Morphogen Axes in the Zebrafish Retina.
Müller glia are instrumental macroglia of the vertebrate retina, once thought to be a homogeneous population. Now Müller glia are generally accepted as transcriptionally heterogeneous, and new evidence suggests functional diversity may exist in the way these cells respond to retinal injury. It remains unclear, however, whether this functional heterogeneity is limited to a transient phenotype that stems from injury or a fundamental feature of the healthy retina. Here, we investigate Müller glia heterogeneity in the uninjured zebrafish retina across development and adulthood using a comprehensive single-cell transcriptomic atlas of the 5 days post-fertilization (dpf) eye, validated in vivo and integrated with 9 dpf and adult datasets. We reveal three constitutive subpopulations of Müller glia that persist from early larval stages into adulthood: (1) a proliferative and immature population in both the peripheral and central retina; (2) a novel cohort of neuron-associated Müller glia that express coherent transcriptional programs specific to distinct neuronal subtypes, including retinal ganglion, amacrine, and horizontal cells; and (3) spatially distinct Müller glia subsets that appear to define a dorso-ventral axis of retinoic acid metabolism, bisected by a novel cyp26c1-expressing equatorial domain. Finally, cross-species analysis reveals that while neuron-associated programs are evolutionarily conserved in mammals, the spatial patterning of morphogens in adult retinae may be specific to the teleost lineage. Collectively, these findings provide robust evidence for intrinsic functional heterogeneity in the uninjured vertebrate retina, reframing Müller glia from a general support population to a specialized cellular network that actively maintains retinal geography and function.
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Histopathology-guided multimodal pathomics identifies a PLEKHA6-positive epithelial state associated with phosphoinositide metabolism in esophageal cancer.
Esophageal cancer is biologically heterogeneous, and conventional clinicopathological staging incompletely captures variation in patient outcomes. This study aimed to determine whether histopathology-derived features associated with phosphoinositide metabolism could support exploratory prognostic stratification and identify biologically interpretable epithelial states. Diagnostic whole-slide images and bulk transcriptomic data from The Cancer Genome Atlas Esophageal Carcinoma (TCGA-ESCA) cohort were integrated with single-cell RNA-sequencing data. Tissue-rich image tiles underwent manual quality control, deep features were extracted using an ImageNet-pretrained ResNet-50 model, and phosphoinositide metabolism activity was quantified by single-sample gene set enrichment analysis (ssGSEA). Associated image features were evaluated using machine-learning survival models, followed by clinicopathological adjustment and multimodal molecular characterization. The selected random survival forest plus gradient boosting machine model stratified overall survival in the training and internal validation cohorts, with concordance indices of 0.762 and 0.723, respectively. The standardized pathology-derived risk score remained associated with overall survival after adjustment for age, sex, histological subtype, and pathological stage (hazard ratio, 2.37; 95% confidence interval, 1.60-3.50). However, calibration was imperfect, and performance estimates may be optimistic because the internal validation cohort informed model selection. Most initial pathology-phosphoinositide metabolism associations were attenuated after adjustment for histological subtype. Multimodal analyses prioritized PLEKHA6 as a candidate pathology-associated epithelial-state marker rather than a subtype-independent prognostic biomarker. PLEKHA6-positive epithelial cells exhibited inflammatory and microenvironment-related transcriptional programs, predicted midkine- and macrophage migration inhibitory factor-related communication features, and stronger inferred copy-number variation-like signals. Higher tumor-level PLEKHA6 expression was also associated with distinct inferred immune, metabolic, and predicted drug-response profiles, although malignant-cell identity was not established. Because the analyzed tiles were not derived from pathologist-annotated malignant regions, the image signal represents composite diagnostic-slide tissue context. These findings identify an exploratory pathology-derived prognostic signal and a PLEKHA6-associated epithelial state in esophageal cancer that require independent, subtype-specific, pathological, and experimental validation.