Immune Microenvironment Research Articles (Page 1)

Single-cell sequencing reveals the immune microenvironment in osteoarthritis: from heterogeneity to therapeutic targets.

Therapeutic potentials of mesenchymal stem cells and their extracellular vesicles on liver diseases by modulating mitochondrial function of macrophages.

Phytochemicals from Stellera chamaejasme alleviate psoriasis by modulating the immune microenvironment via the JAK2/PI3K/AKT pathway.

The ferroptosis-associated gene TIMP1 facilitates skin scar formation through the interaction with CST3 in fibroblasts.

Targeting annexin A2 enhances anti-PD-1 immunotherapy in pancreatic ductal adenocarcinoma by remodeling the tumor immune microenvironment.

Construction and multi-omics analysis of ccRCC mitochondrial related gene machine learning model and validate of key gene FKBP10.

Evidence for the association between rheumatoid arthritis (RA) and osteoporosis (OP) remains inconsistent, and the role of inflammatory cytokines in mediating this association remains unclear. This study used linkage disequilibrium score regression (LDSC), Mendelian randomization (MR), and colocalization analyses to assess the association between RA and OP. Mediation MR analysis was conducted to explore the mediating role of inflammatory cytokines. Multitrait analysis of GWAS enhanced statistical power and identified novel genetic associations. Independent risk loci were examined using GCTA-COJO, PLACO, and FUMA analyses. Risk-associated genes were identified by integrated MAGMA, SMR, and TWAS methods, while BLISS analysis revealed relevant proteins. The GEO database was used to validate pleiotropic gene expression. Genetic correlation (rg = 0.171), causal association (OR = 1.103), and colocalization analysis (PPH4 = 0.99) together confirmed a genetic link between RA and OP. Interleukin (IL)-17 mediated the RA-OP association. The SNPs rs11574914 and rs11889341 are MTAG-RA independent risk loci. Twenty-five RA-related risk genes are specifically expressed in the lymph node and tonsils. FCRL3 regulates the RA immune infiltration microenvironment. IL-17 promotes the progression of RA to OP; FCRL3 regulates the immune infiltration microenvironment of RA and is a potential therapeutic target. Key Points • Genetic correlation, MR, and colocalization analyses confirm a shared genetic basis between RA and OP. •IL-17 is identified as a key inflammatory mediator driving the progression from RA to OP. •Multi-trait GWAS and integrative post-GWAS analyses uncover novel RA-specific loci and 25 immune-related risk genes. •FCRL3 regulates immune cell infiltration in RA and emerges as a potential therapeutic target for inflammation-induced bone loss.

Chronic glomerulonephritis is a prevalent renal disorder in clinical practice. A metabolic imbalance in copper, a vital trace element in the human body, is potentially linked to a myriad of diseases. Consequently, this study aimed to elucidate the role of copper metabolism in the onset and progression of chronic glomerulonephritis. Public microarray datasets gene expression omnibus series(GSE) 66494, GSE32591, and GSE116626 were procured from the gene expression omnibus database, encompassing clinical information on chronic glomerulonephritis and normal kidney tissues. Differential gene expression analysis was conducted, followed by the intersection of the differentially expressed genes from the 3 datasets with those related to copper metabolism. Furthermore, STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network; PPI hub genes were identified via the cytoHubba plugin, and gene set enrichment analysis was performed. Tissues were subsequently collected from chronic glomerulonephritis patients at our hospital; hematoxylin and eosin, periodic acid-silver methenamine, and Masson staining were conducted; and transmission electron microscopy was performed. Pivotal genes were selected for real time quantitative polymerase chain reaction (PCR) (RT-qPCR) validation, and serum copper ion levels were measured. Additionally, CIBERSORT analysis was employed to assess immune cell infiltration and its correlation with pivotal genes. Differential gene expression analysis revealed 25 differentially expressed copper metabolism-related genes (CMRGs), comprising 11 upregulated genes and 14 downregulated genes. PPI network construction and gene correlation analysis ultimately identified aconitase (ACO1) and superoxide dismutase (SOD2) as pivotal genes for RT-qPCR validation. The results demonstrated that ACO1 was expressed at low levels in lupus nephritis tissues, whereas SOD2 was highly expressed in immunoglobulin A nephropathy and diabetic nephropathy tissues. Moreover, immune infiltration analysis revealed that diverse immune cell types, including T cells, B cells, and macrophages, are intricately associated with the onset and progression of chronic glomerulonephritis in patient tissues. Differential and correlation analyses of CMRGs revealed that T cells, plasma cells, and monocyte-macrophages are involved in the biological processes of copper metabolism. This study suggests that the CMRGs ACO1 and SOD2 may modulate the inflammatory response and immune microenvironment in chronic glomerulonephritis by regulating immune cell activation and function, thereby facilitating disease progression.

Despite advancements in early detection and treatment, liver cancer (LC) remains highly recurrent due to its complex immunosuppressive tumor microenvironment (TME), leading to poor prognosis in advanced stages. Nanomedicines (NMs) offer novel therapeutic strategies for reversing the immunosuppressive TME in LC. This review systematically analysed the diverse mechanisms contributing to immunosuppressive TME formation and explored the potential of smart responsive NMs in targeted drug delivery, immune remodeling, and multimodal therapy. The immunosuppressive TME in LC arises from abnormal physiological conditions, extracellular matrix (ECM) deposition, dysfunction of antigen-presenting cells, exhaustion of T cells, infiltration of immunosuppressive cells, metabolic reprogramming, and microbiota influences. Smart NMs can overcome delivery barriers through passive targeting and ligand-directed active targeting to LC cells via receptors, as well as to immunosuppressive cell populations. NMs can respond to endogenous and exogenous stimuli, enabling precise spatiotemporal drug release. This feature enables integration of chemotherapy, immunotherapy, and physical therapies. Additionally, NMs can reprogram the TME by remodeling physiological conditions, inhibiting ECM deposition, regulating metabolism, inducing immunogenic cell death, and modulating microbiota-derived metabolites. Although toxicity and clinical translation still require further optimization, smart NMs offer a paradigm shift for LC therapy through an integrated "targeted delivery-immune reprogramming" strategy.

The prognostic role of tumor proliferation in colorectal cancer (CRC) has been unclear, while T cell proliferation has been associated with favorable outcome. We investigated characteristics and prognostic significance of proliferating tumor and cytotoxic T cells. Two independent CRC cohorts comprising 1839 patients were analyzed using multiplex immunohistochemistry for MKI67 (Ki-67), CD8, and CK. Densities and spatial localization of MKI67+ and MKI67- cytotoxic T cells and tumor proliferation rate were assessed via digital image analysis. Single-cell RNA sequencing data from 62 colon cancers were used to characterize proliferating and non-proliferating cells. High MKI67+ tumor cell percentage was associated with better cancer-specific survival, an anti-tumorigenic immune microenvironment, downregulation of epithelial mesenchymal transition, and upregulation of MYC signaling. In the larger cohort, the multivariable HR for high vs. low proliferation rate was 0.60 (95%CI 0.43-0.83). MKI67+CD8+ T cells exhibited high expression of effector molecules such as GZMB and IFNG and stronger association with favorable prognosis than MKI67-CD8+ T cells. The multivariable HR for high vs. low MKI67+CD8+ T cell density was 0.49 (95%CI 0.35-0.70). However, spatial analysis of tumor cell-T cell co-localization indicated comparable prognostic significance for both subsets when considering their proximity to tumor cells. Tumor cell proliferation is a marker for better prognosis in CRC. Although proliferating cytotoxic T cells demonstrate stronger prognostic value than non-proliferating cytotoxic T cells, spatial proximity to tumor cells diminishes this difference. These findings provide new insights into the interplay between tumor proliferation, immune response, and patient outcomes in CRC.

Effective antitumor immunity ultimately depends on the priming and activation of tumor-specific cytotoxic CD8+ T cells; however, the role of intratumoral cell-cell immune interactions remains incompletely understood. Recent work has revealed that the temporospatial colocalization of dendritic cells (DCs), helper T cells (Th), and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. Herein, we report the integration of more than one million spatially resolved single-cell profiles across six spatial proteomic and transcriptomic assays, which demonstrated that DC:Th:CTL three-cell-type clusters were common even in immunotherapy-naïve and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma (PDAC). We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules (mregDC), CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary PDAC tumors showed that the density of antigen-presenting cell (APC):Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.

Exosome-mediated molecular processes significantly influence bladder cancer (BCa) development, but clinically applicable exosome-based prognostic systems are still lacking. This research aims to develop an exosome-related prognostic model using machine learning approaches and discover potential therapeutic targets. We implemented ten machine learning algorithms with eighty-one combinatorial configurations to analyze BCa transcriptomic data. Model validation incorporated time-dependent receiver operating characteristic analysis, Kaplan-Meier survival curves, nomogram assessment, and Cox regression. Biological mechanisms were explored through immune microenvironment evaluation (CIBERSORT) and functional enrichment analysis (GSEA). Molecular docking using PubChem, PDB structures, and CB-DOCK2 identified potential targets, followed by experimental validation including quantitative reverse transcription PCR (qRT-PCR), Western Blotting (WB), cell proliferation (CCK-8, colony formation), migration (Transwell, wound healing), EMT marker detection, and tail vein injection-based lung metastasis assays in nude mice. Analysis revealed 132 differentially expressed genes specific to BCa, which were subsequently refined to 15 prognosis-associated genes through univariate Cox regression. The machine learning-derived prognostic model (MLDPM) outperformed existing clinical indicators, effectively stratifying patients into distinct risk categories. High-risk patients demonstrated characteristics of immune evasion and poorer survival outcomes. Computational docking analysis identified strong molecular interactions between THBS1/MMP9/CXCL12 and standard chemotherapeutic compounds. Importantly, suppression of THBS1 expression significantly inhibited BCa cell migration and invasion. This study establishes the first machine learning-based exosomal prognostic system for BCa and identifies THBS1 as both a potential biomarker and therapeutic target. The combined computational and experimental methodology offers a new approach for personalized BCa treatment strategies.

The emergence of two-dimensional (2D) nanomaterials such as MXenes has significantly expanded opportunities in precision oncology. With their high surface area, tunable surface chemistry, strong photothermal conversion efficiency, and intrinsic biocompatibility, MXenes offer promising potential for cancer nanotheranostics. This review explores the therapeutic applications of MXenes, focusing on their dual roles in direct tumor ablation and modulation of the tumor immune microenvironment (TIME). MXenes exert anticancer effects through reactive oxygen species-mediated cytotoxicity and localized photothermal heating while also influencing immune cell function and tumor-immune interactions. Recent studies using single-cell sequencing and high-dimensional immune profiling highlight the capacity of MXenes to modulate immune-mediated tumor cell death. Their selective reactivity in the acidic tumor milieu, linked to the Warburg effect, makes them ideal candidates for pH-responsive drug delivery. We further discuss synergistic strategies combining MXene-based photothermal therapy with chemotherapy, targeted agents, and immunotherapies. Advancing MXene-based cancer therapies requires an integrated understanding of tumor biology, metabolic reprogramming, and TIME dynamics. This multidisciplinary approach is essential for the development of safe, selective, and personalized nanomedicine platforms.

Introduction The N6-methyladenosine (m6A)-related competing endogenous RNA (ceRNA) network plays a critical role in the occurrence and progression of lung adenocarcinoma (LUAD). This study aimed to investigate the characteristics of m6A-related ceRNAs. Material and methods Gene expression matrices and clinical data were obtained from The Cancer Genome Atlas (TCGA) database, along with the GSE176348 dataset sourced from the Gene Expression Omnibus (GEO) database. Differential expression analysis was performed using the “GEO2R” tool and the “limma” R package to identify differentially expressed genes (DEGs). By integrating results from CIBERSORTx and m6A-related databases, we further identified m6A-associated and immune-related genes. The tumor immune microenvironment (TIME) was characterized utilizing the TIMER and TISIDB databases. Finally, differential expression of key molecules between LUAD and normal lung tissues was validated through polymerase chain reaction (PCR). Results We found 220 DEGs related to multiple classical tumor pathways using the DAVID and Metascape databases, such as regulation of ERK1, ERK2 cascade, PI3K-AKT signaling pathway and regulation of cell adhesion. By combining the m6A and CIBERSORTx databases, we selected ANGPT1, which was involved in the PI3K-AKT pathways. ANGPT1 expression was lower in LUAD cells than in normal lung cells and associated with patients’ prognosis (p < 0.01). ANGPT1 expression was correlated with PD-L1 (p < 0.01) and multiple immune cells. The PCR results showed that ANGPT1 was expressed at significantly lower levels in A549 cells than in BEAS-2B cell lines. Conclusions A validated signature of the m6A-related ceRNA network demonstrated prognostic utility for predicting survival and provides new insights into potential novel therapeutic targets.

Endometrial cancer is the sixth most common cancer in women worldwide and the fourth most common cancer in women in the United States. In the United States, its incidence and mortality rates have continued to increase since the late 1990s. Endometrial cancer comprises most uterine corpus carcinomas and represents a heterogeneous group of cancers varying in pathology, histology, molecular biology, immunogenicity, and prognosis. Recently, the advancement of molecular classification and subsequent clinical trials have led to new FDA approvals for the use of immune checkpoint inhibitors in endometrial cancer. However, recurrent and advanced-stage endometrial cancer continues to demonstrate high morbidity and mortality, denoting an unmet need for innovative immunotherapeutic strategies. This review explores current concepts in the endometrial cancer tumor immune microenvironment, comparing antigenicity, immunosurveillance, and immunoregulation among molecular and histologic subtypes and providing insight into which subtypes may be particularly responsive to immunotherapy. Novel immunotherapeutic strategies targeting cancer antigens, emerging immune checkpoints, immunomodulatory cytokines, and tumor-infiltrating immune cells are described, and corresponding clinical trials are presented. Integrated approaches such as immunogenic modulation, which enhances tumor susceptibility to immune attack, and immune subset conditioning, which modifies suppressive immune components within the tumor immune microenvironment, are presented as promising avenues to render "cold" tumors responsive. Together, the immunotherapies reviewed here offer potential strategies for treating patients with advanced or refractory endometrial cancer.

Metabolic syndrome is a major risk factor for hepatocellular carcinoma (HCC) progression, yet the role of metabolic syndrome-related genes in HCC remains incompletely understood. Using bioinformatics approaches, we investigated the influence of these genes on HCC prognosis and tumor biology. Two distinct patient clusters (C1 and C2) were identified based on metabolic gene expression, with C2 exhibiting poorer survival, increased stemness, and higher risk scores. A risk model further revealed that high-risk patients had worse outcomes, elevated immunosuppressive cell infiltration, and distinct phenotypic features. Experimental validation via qRT-PCR confirmed upregulation of risk model genes (particularly KIAA1841 and TUBA1B) in HCC cell lines and patient blood samples. Notably, post-surgical declines in KIAA1841 and TUBA1B levels were observed. Our findings highlight the clinical relevance of metabolic syndrome-related genes in HCC, linking them to prognosis, tumor microenvironment remodeling, cancer stemness, and immunotherapy response.

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan–Meier survival plots, receiver operating characteristic (ROC) curves, and principal component analysis. Survival analysis demonstrated that specific TAM signature gene expressions serve as significant prognostic markers, identifying TAM signatures positively correlated with patient survival and macrophage infiltration. A 27-gene TAM risk model was established, successfully stratifying patients into risk categories, with low-risk patients showing improved overall survival. These findings provide insights into the role of TAMs in modulating the RCC tumor immune microenvironment and their impact on patient prognosis, suggesting that TAM-based signatures may serve as useful prognostic markers and potential targets to enhance RCC treatment strategies.

Unraveling the therapeutic potential of triptolide in glioma: Orchestrating apoptosis and immune landscape remodeling.

The role of tumor-infiltrating lymphocytes (TILs) remains unclear in hormone receptor (HR)-positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences. Patients with stage I-III HR-positive/HER2-negative tumors were identified from a prospective cohort study of breast cancer patients diagnosed at age ≤ 40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non-CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer-free survival (iBCFS), distant disease-free survival (DDFS), and overall survival (OS), adjusted for clinicopathologic parameters. Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histological subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non-CD8 T cell infiltration, T regulatory cell infiltration, and PDL1 expression was associated with improved iBCFS. Higher intratumoral non-CD8 T cell infiltration, T regulatory cell infiltration, and PDL1 expression was associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T cell infiltration and PDL1 expression was associated with improved OS. Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization.

The nucleic acid metabolism process is driven by various carcinogenic factors, providing a material basis and energy guarantee for the malignant phenotype of tumor cells. However, the role of nucleic acid metabolism in triple-negative breast cancer (TNBC) development remains unclear. Here, we examined the expression patterns of nucleic acid metabolism-related genes (NAMRGs) in the transcriptome of 297 TNBC samples derived from three datasets. We used single-cell RNA sequencing analysis and both in vivo and in vitro experiments to verify the correlation between NAMRGs and tumor metastasis and tumor immune matrix microenvironment (TME) characteristics. According to the results, two different molecular subtypes were identified, and the relationships between the molecular subtypes, four genetic subtypes, and four pathological subtypes were established. Changes in nucleic acid metabolism were related to changes in homologous recombination repair defects (HRD), cell infiltration in the TME, and patient prognosis. We also constructed a prediction model, NAM_model, by including four NAMRGs (DPYD, PDE6G, PDE8B, and TYMS) and integrating it with other clinical indicators. This model was a highly accurate prognostic nomogram, which showed that the prognosis of high-risk patients was poor, with NAMRGs associated with TME immune exhaustion. In addition, NAMRGs were significantly correlated with drug sensitivity to chemotherapy and targeted therapy. In vivo and in vitro studies have shown that PDE8B is an oncogene that promotes tumor growth and induces TNBC metastasis by promoting epithelial-mesenchymal transition (EMT), which has not been reported previously. Single-cell RNA sequencing also revealed the unique effects of nucleic acid metabolism and HRD on exhausted CD8+ T cells. A comprehensive analysis of NAMRGs revealed the potential impact of nucleic acid metabolism-mediated mechanisms, such as HRD and EMT, on the clinical pathological characteristics, TME characteristics, and prognosis of patients with TNBC. These findings have deepened our understanding of the roles of NAMRGs in TNBC and immunotherapy, which will greatly contribute to patient stratification management and individualized clinical decision-making.